Compositions and methods for the treatment and prevention of neurological disorders

ABSTRACT

The invention provides compositions and methods for treating neurological disorders, such as amyotrophic lateral sclerosis, frontotemporal degeneration, and Alzheimer&#39;s disease, among others. Using the compositions and methods described herein, a patient having a neurological disorder, such as a neurological disorder associated with TAR-DNA binding protein (TDP)-43 aggregation, may be administered an inhibitor of cytochrome P450 (CYP450) isoform 51A1 (CYP51A1), also referred to herein as lanosterol 14-alpha demethylase, so as to treat an underlying etiology of the disorder and/or to alleviate one or more symptoms of the disease. The inhibitor of CYP51A1 may be a small molecule, anti-CYP51A1 antibody or antigen-binding fragment thereof, or a compound, such as an interfering RNA molecule, that attenuates CYP51A1 expression. Patients that may be treated using the compositions and methods described herein include those that express a mutant TDP-43 isoform containing a mutation associated with TDP-43-promoted aggregation and toxicity.

SEQUENCE LISTING

The instant application contains a Sequence Listing which has beensubmitted electronically in ASCII format and is hereby incorporated byreference in its entirety. Said ASCII copy, created on Jun. 19, 2019, isnamed 51061-029002_Sequence_Listing_6.19.19_ST25 and is 18,129 bytes insize.

FIELD OF THE INVENTION

The invention relates to the field of therapeutic treatment ofneurological disorders in patients, such as human patients.

BACKGROUND OF THE INVENTION

Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease,is an aggressive, debilitating neurological disorder in which affectedpatients succumb within 2 to 5 years after diagnosis. ALS presents withheterogeneous clinical features but has a common underlying pathology ofmotor neuron loss that limits the central nervous system's ability toeffectively regulate voluntary and involuntary muscle activity.Additionally, without neuronal trophic support muscles being to atrophy,further exacerbating motor deterioration. Cellular and tissuedegeneration results in motor impairment such as fasciculations andweakening in the arms, legs and neck, difficulty swallowing, slurredspeech and ultimately failure of the diaphragm muscles that controlbreathing. There remains a need for a treatment paradigm for ALS, aswell as various other neurological disorders.

SUMMARY OF THE INVENTION

The present disclosure relates to compositions and methods for treatingneurological disorders, such as amyotrophic lateral sclerosis, amongothers, including neuromuscular disorders and various other neurologicalconditions. Using the compositions and methods described herein, apatient having a neurological disorder, such as amyotrophic lateralsclerosis, frontotemporal degeneration (also referred to asfrontotemporal lobar degeneration and frontotemporal dementia),Alzheimer's disease, Parkinson's disease, dementia with Lewy Bodies,corticobasal degeneration, progressive supranuclear palsy, dementiaparkinsonism ALS complex of Guam, Huntington's disease, Inclusion bodymyopathy with early-onset Paget disease and frontotemporal dementia(IBMPFD), sporadic inclusion body myositis, myofibrillar myopathy,dementia pugilistica, chronic traumatic encephalopathy, Alexanderdisease, or hereditary inclusion body myopathy may be administered aninhibitor of cytochrome P450 (CYP450) isoform 51A1 (CYP51A1), alsoreferred to herein as lanosterol 14-alpha demethylase, so as to treat anunderlying etiology of the disorder and/or to alleviate one or moresymptoms of the disease.

The inhibitor of CYP51A1 may be, e.g., a small molecule, such asLEK-935, CP-320626, itraconazole, posaconazole, cyproconazole,voriconazole, fluconazole, clotrimazol, fenticonazole, epoxiconazole,ketoconazole, ravuconazole, isavuconazole, holothurin A, theasaponin,capsicosine, betulafolientriol, prochloraz, propiconazole,prothioconazole, prothioconazole-desthio, tebuconazole, triadimenol,azalanstat, or a variant thereof. In some embodiments, the CYP51A1inhibitor is an anti-CYP51A1 antibody or antigen-binding fragmentthereof, or a compound, such as an interfering RNA molecule, thatattenuates CYP51A1 expression.

Patients that may be treated using the compositions and methodsdescribed herein include those that exhibit, and/or that are prone todevelop, aggregation of TAR-DNA binding protein (TDP)-43. Example ofpatients that may exhibit or may be prone to exhibit TDP-43 aggregationare those that express a mutant TDP-43 isoform containing a mutationthat renders this protein susceptible to aggregation. For example,patients that may be treated using the compositions and methodsdescribed herein include those expressing a TDP-43 isoform having amutation selected from Q331K, M337V, Q343R, N345K, R361S, and N390D,among others that are associated with TDP-43 aggregation and toxicity invivo.

In a first aspect, the invention features a method of treating aneurological disorder in a patient, such as a human patient, byproviding to the patient a therapeutically effective amount of a CYP51A1inhibitor.

In another aspect, the invention features a method of treating aneurological disorder in a patient, such as a human patient, identifiedas likely to benefit from treatment with a CYP51A1 inhibitor on thebasis of TDP-43 aggregation. In this aspect, the method may include (i)determining that the patient exhibits, or is prone to develop, TDP-43aggregation, and (ii) providing to the patient a therapeuticallyeffective amount of a CYP51A1 inhibitor. In some embodiments, thepatient has previously been determined to exhibit, or to be prone todeveloping, TDP-43 aggregation, and the method includes providing to thepatient a therapeutically effective amount of a CYP51A1 inhibitor. Thesusceptibility of the patient to developing TDP-43 aggregation may bedetermined, e.g., by determining whether the patient expresses a mutantisoform of TDP-43 containing a mutation that is associated with TDP-43aggregation and toxicity, such as a mutation selected from Q331K, M337V,Q343R, N345K, R361S, and N390D. This may be performed, for example, bydetermining the amino acid sequence of a TDP-43 isoform isolated from asample obtained from the patient or by determining the nucleic acidsequence of a TDP-43 gene isolated from a sample obtained from thepatient. In some embodiments, the method includes the step of obtainingthe sample from the patient.

In an additional aspect, the invention features a method of treating aneurological disorder in a patient, such as a human patient, identifiedas likely to benefit from treatment with a CYP51A1 inhibitor on thebasis of TDP-43 expression. In this aspect, the method includes (i)determining that the patient expresses a mutant form of TDP-43 having amutation associated with TDP-43 aggregation (e.g., a mutation selectedfrom Q331K, M337V, Q343R, N345K, R361S, and N390D), and (ii) providingto the patient a therapeutically effective amount of a CYP51A1inhibitor. In some embodiments, the patient has previously beendetermined to express a mutant form of TDP-43 having a mutationassociated with TDP-43 aggregation, such as a Q331K, M337V, Q343R,N345K, R361S, or N390D mutation, and the method includes providing tothe patient a therapeutically effective amount of a CYP51A1 inhibitor.

In another aspect, the invention features a method of determiningwhether a patient (e.g., a human patient) having a neurological disorderis likely to benefit from treatment with a CYP51A1 inhibitor by (i)determining whether the patient exhibits, or is prone to develop, TDP-43aggregation and (ii) identifying the patient as likely to benefit fromtreatment with a CYP51A1 inhibitor if the patient exhibits, or is proneto develop, TDP-43 aggregation. In some embodiments, the method furtherincludes the step of (iii) informing the patient whether he or she islikely to benefit from treatment with a CYP51A1 inhibitor. Thesusceptibility of the patient to developing TDP-43 aggregation may bedetermined, e.g., by determining whether the patient expresses a mutantisoform of TDP-43 containing a mutation that is associated with TDP-43aggregation and toxicity, such as a mutation selected from Q331K, M337V,Q343R, N345K, R361S, and N390D. This may be performed, for example, bydetermining the amino acid sequence of a TDP-43 isoform isolated from asample obtained from the patient or by determining the nucleic acidsequence of a TDP-43 gene isolated from a sample obtained from thepatient. In some embodiments, the method includes the step of obtainingthe sample from the patient.

In another aspect, the invention features a method of determiningwhether a patient (e.g., a human patient) having a neurological disorderis likely to benefit from treatment with a CYP51A1 inhibitor by (i)determining whether the patient expresses a TDP-43 mutant having amutation associated with TDP-43 aggregation (e.g., a mutation selectedfrom Q331K, M337V, Q343R, N345K, R361 S, and N390D) and (ii) identifyingthe patient as likely to benefit from treatment with a CYP51A1 inhibitorif the patient expresses a TDP-43 mutant. In some embodiments, themethod further includes the step of (iii) informing the patient whetherhe or she is likely to benefit from treatment with a CYP51A1 inhibitor.The TDP-43 isoform expressed by the patient may be assessed, forexample, by isolated TDP-43 protein from a sample obtained from thepatient and sequencing the protein using molecular biology techniquesdescribed herein or known in the art. In some embodiments, the TDP-43isoform expressed by the patient is determined by analyzing thepatient's genotype at the TDP-43 locus, for example, by sequencing theTDP-43 gene in a sample obtained from the patient. In some embodiments,the method includes the step of obtaining the sample from the patient.

In some embodiments of any of the above aspects, the CYP51A1 inhibitoris provided to the patient by administration of the CYP51A1 inhibitor tothe patient. In some embodiments, the CYP51A1 inhibitor is provided tothe patient by administration of a prodrug that is converted in vivo tothe CYP51A1 inhibitor.

In some embodiments of any of the above aspects, the neurologicaldisorder is a neuromuscular disorder, such as a neuromuscular disorderselected from amyotrophic lateral sclerosis, congenital myasthenicsyndrome, congenital myopathy, cramp fasciculation syndrome, Duchennemuscular dystrophy, glycogen storage disease type II, hereditary spasticparaplegia, inclusion body myositis, Isaac's Syndrome, Kearns-Sayresyndrome, Lambert-Eaton myasthenic syndrome, mitochondrial myopathy,muscular dystrophy, myasthenia gravis, myotonic dystrophy, peripheralneuropathy, spinal and bulbar muscular atrophy, spinal muscular atrophy,Stiff person syndrome, Troyer syndrome, and Guillain-Barré syndrome. Insome embodiments, the neurological disorder is amyotrophic lateralsclerosis.

In some embodiments of any of the above aspects, the neurologicaldisorder is selected from frontotemporal degeneration (also referred toas frontotemporal lobar degeneration and frontotemporal dementia),Alzheimer's disease, Parkinson's disease, dementia with Lewy Bodies,corticobasal degeneration, progressive supranuclear palsy, dementiaparkinsonism ALS complex of Guam, Huntington's disease, Inclusion bodymyopathy with early-onset Paget disease and frontotemporal dementia(IBMPFD), sporadic inclusion body myositis, myofibrillar myopathy,dementia pugilistica, chronic traumatic encephalopathy, Alexanderdisease, and hereditary inclusion body myopathy.

In some embodiments of any of the above aspects, the CYP51A1 inhibitoris a small molecule antagonist of CYP51A1 activity. The CYP51A1inhibitor may be, for example, a compound represented by formula (I)

wherein n is 1 or 2;

X is hydrogen, lower alkyl, lower alkoxy-lower alkyl, or a group X_(a)of the formula:

Z is a group of the formula:

Y is a group of the formula:

R_(O) is lower alkyl, COR₄ or C(R₅)═CHCOR₄;

R is R_(o) or is OR″;

R″ is hydrogen, lower-alkyl, lower alkanoyl, (CH₂)₁₋₆—OH,(CH₂)₁₋₆—O(CH₂)₁₋₆—R₆, or (CH₂)₁₋₆—COR₄;

R₁ and R_(a) are hydrogen, lower alkanoyl, benzoyl or (CH₂)₁₋₆—OH;

R₂ and R^(b) are hydrogen, Cl, Br or CF₃;

R₃ and R₅ are hydrogen or CH₃;

R₄ is hydroxy, lower-alkoxy or N(R₇, R₈);

R₆ is hydrogen, R_(g), OH or COR₄;

R₇ and R₈ are hydrogen or lower alkyl;

R_(c) and R_(e) are hydrogen, Cl, F, Br or CF₃;

R_(d) is hydrogen or NH₂;

R_(f) is hydrogen, CH₃CONH—, NH₂COCH₂— or R₉CH₂CH₂OCH₂CH₂O—;

R_(g) and R₉ are phenyl or phenyl substituted by Cl, F or Br;

or a pharmaceutically acceptable salt, ester, or ether thereof.

In some embodiments of formula (I), n is 1, R₁ is hydrogen, R₂ ischlorine in the 6-position of a 2-pyridyl residue and Y is phenylsubstituted in the p-position by R.

In some embodiments of formula (I), X is X^(a); R^(a) is hydrogen; Z is6-chloro-2-pyridyl, and Y is phenyl substituted in the p-position by2-ethoxyethoxy, 2-phenethoxyethoxy or methoxycarbonylmethoxy.

In some embodiments of formula (I), the compound is methylα,α′-[[[(R)-p-(2-ethoxyethoxy)-α-methylphen-ethyl]imino]dimethylene]bis[(RS)-6-chloro-2-pyridinemethanol];(RS)-6-chloro-α-[[[(R)-p-(2-ethoxyethoxy)-α-methyl-phenethyl]amino]methyl]-2-pyridinemethanol;α,α′-[[[p-(2-ethoxyethoxy)phenethyl]imino]dimethylene]bis[(RS)-6-chloro-2-pyridinemethanol];(R)-6-bromo-α-[[[(RS)-2-(6-bromo-2-pyridyl)-2-hydroxyethyl][(R)-p-(2-ethoxyethoxy)-α-methylphenethyl]amino]methyl]-2-pyridimidinemethanol;(R)-6-chloro-α[[[(S)-2-(6-chloro-2-pyridyl)-2-hydroxyethyl][(R)-.alpha.-methyl-p-(2-phenethoxyethoxy)phenethyl]amino]methyl]-2-pyridinemethanol,or a pharmaceutically acceptable salt, ester, or ether thereof.

In some embodiments, the CYP51 A1 inhibitor is a compound represented byformula (II)

wherein n is 1, 2, 3, or 4 and m is 0, 1, 2, 3, 4, or 5;

R₁ is a hydrogen atom, hydroxyl group, or lower C₁₋₆ alkoxy group;

R₂ is a hydrogen atom or an optionally substituted straight or branchedlower C₁₋₆ alkyl group (e.g., an aryl lower alkyl group, such as aphenyl lower alkyl group); and

each X is independently fluorine, chlorine, bromine, hydroxyl group,trifluoromethyl group, 3,4-di-Cl, 2,4-di-Cl or lower C₁₋₆ alkoxy group,and wherein the phenyl ring containing the X is optionally fused (so asto form, e.g., a naphthyl ring);

or a pharmaceutically acceptable salt, ester, or ether thereof.

In some embodiments, the CYP51A1 inhibitor is a compound represented byformula (1), (2), (3), (13), (14), (15), or (16)

or a pharmaceutically acceptable salt, ester, or ether thereof.

In some embodiments, n is an integer 2, R₁ is a hydroxyl group, R₂ amethyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl group and X is ahydrogen atom or phenyl disubstituted with two chlorine atoms in thepositions 3 and 4 or in the positions 2 and 4.

In some embodiments, the CYP51A1 inhibitor is a compound represented byformula (III)

wherein the dotted line (

) is an optional bond;

X is O or S;

A is —C(H)═, —C((C₁-C₄)alkyl)═, —C(halo)═ or —N═, when the dotted line (

) is a bond, or A is methylene or —CH((C₁-C₄)alkyl)—, when the dottedline (

) is not a bond;

R₁, R₁₀ and R₁₁ are each independently H, halo, cyano, 4-, 6-, or7-nitro, (C₁-C₄)alkyl, (C₁-C₄)alkoxy, fluoromethyl, difluoromethyl ortrifluoromethyl;

R₂ is H;

R₃ is H or (C₁-C₆)alkyl;

R₄ is H, methyl, ethyl, n-propyl, hydroxy(C₁-C₃)alkyl,(C₁-C₃)alkoxy(C₁-C₃)alkyl, phenyl(C₁-C₄)alkyl,phenylhydroxy(C₁-C₄)alkyl, (phenyl)((C₁-C₄)-alkoxy)(C₁-C₄)alkyl,thien-2- or -3-yl(C₁-C₄)alkyl or fur-2- or 3-yl(C₁-C₄)alkyl wherein theR₄ rings are mono-, di- or tri-substituted independently on carbon withH, halo, (C₁-C₄)alkyl, (C₁-C₄)alkoxy, trifluoromethyl, hydroxy, amino,cyano or 4,5-dihydro-1H-imidazol-2-yl; or

R₄ is pyrid-2-, -3- or -4-yl(C₁-C₄)alkyl, thiazol-2-, -4- or-5-yl(C₁-C₄)alkyl, imidazol-2-, -4- or -5-yl(C₁-C₄)alkyl, pyrrol-2- or-3-yl(C₁-C₄)alkyl, oxazol-2-, -4- or -5-yl(C₁-C₄)alkyl, pyrazol-3-, -4-or -5-yl(C₁-C₄)alkyl, isoxazol-3-, -4- or -5-yl(C₁-C₄)alkyl,isothiazol-3-, -4- or -5-yl(C₁-C₄)alkyl, pyridazin-3- or-4-yl(C₁-C₄)alkyl, pyrimidin-2-, -4-, -5- or -6-yl(C₁-C₄)alkyl,pyrazin-2- or -3-yl(C₁-C₄)alkyl, 1,3,5-triazin-2-yl(C₁-C₄)alkyl; orindol-2-(C₁-C₄)alkyl, wherein the preceding R₄ heterocycles areoptionally mono- or di-substituted independently with halo,trifluoromethyl, (C₁-C₄)alkyl, (C₁-C₄)alkoxy, amino, hydroxy or cyanoand the substituents are bonded to carbon; or

R₄ is R₁₅-carbonyloxymethyl, wherein the R₁₅ is phenyl, thiazolyl,imidazolyl, 1H-indolyl, furyl, pyrrolyl, oxazolyl, pyrazolyl,isoxazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinylor 1,3,5-triazinyl and wherein the preceding R₁₅ rings are optionallymono- or di-substituted independently with halo, amino, hydroxy,(C₁-C₄)alkyl, (C₁-C₄)alkoxy or trifluoromethyl and the mono- ordi-substituents are bonded to carbon;

R₅ is H, methyl, ethyl, n-propyl, hydroxymethyl or hydroxyethyl;

R₆ is carboxy, (C₁-C₈)alkoxycarbonyl, benzyloxycarbonyl, C(O)NR₈R₉ orC(O)R₁₂ wherein

R₈ is H, (C₁-C₆)alkyl, cyclo(C₃-C₆)alkyl, cyclo(C₃-C₆)alkyl(C₁-C₅)alkyl,hydroxy or (C₁-C₈)alkoxy; and

R₉ is H, cyclo(C₃-C₈)alkyl, cyclo(C₃-C₈)alkyl(C₁-C₅)alkyl,cyclo(C₄-C₇)alkenyl, cyclo(C₃-C₇)alkyl(C₁-C₅)alkoxy,cyclo(C₃-C₇)alkyloxy, hydroxy, methylene-perfluorinated(C₁-C₈)alkyl,phenyl, or a heterocycle wherein the heterocycle is pyridyl, furyl,pyrrolyl, pyrrolidinyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl,pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl, pyranyl,pyridinyl, piperidinyl, morpholinyl, pyridazinyl, pyrimidinyl,pyrazinyl, piperazinyl, 1,3,5-triazinyl, benzothiazolyl, benzoxazolyl,benzimidazolyl, thiochromanyl or tetrahydrobenzothiazolyl wherein theheterocycle rings are carbon-nitrogen linked; or

R₉ is (C₁-C₆)alkyl or (C₁-C₆)alkoxy wherein the (C₁-C₆)alkyl or(C₁-C₈)alkoxy is optionally monosubstituted with cyclo(C₄-C₇)alken-1-yl,phenyl, thienyl, pyridyl, furyl, pyrrolyl, pyrrolidinyl, oxazolyl,thiazolyl, imidazolyl, pyrazolyl, pyrazolinyl, pyrazolidinyl,isoxazolyl, isothiazolyl, pyranyl, piperidinyl, morpholinyl,thiomorpholinyl, 1-oxothiomorpholinyl, 1,1-dioxothiomorpholinyl,pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, 1,3,5-triazinyl orindolyl and wherein the (C₁-C₆)alkyl or (C₁-C₈)alkoxy are optionallyadditionally independently mono- or di-substituted with halo, hydroxy,(C₁-C₅)alkoxy, amino, mono-N— or di-N,N—(C₁-C₅)alkylamino, cyano,carboxy, or (C₁-C₄)alkoxycarbonyl; and

wherein the R₉ rings are optionally mono- or di-substitutedindependently on carbon with halo, (C₁-C₄)alkyl, (C₁-C₄)alkoxy, hydroxy,hydroxy(C₁-C₄)alkyl, amino(C₁-C₄)alkyl, mono-N— ordi-N,N—(C₁-C₄)alkylamino(C₁-C₄)alkyl, (C₁-C₄)alkoxy(C₁C₄)alkyl, amino,mono-N— or di-N,N—(C₁-C₄)alkylamino, cyano, carboxy,(C₁-C₅)alkoxycarbonyl, carbamoyl, formyl or trifluoromethyl and the R₉rings may optionally be additionally mono- or di-substitutedindependently with (C₁-C₅)alkyl or halo;

optionally with the proviso that no quaternized nitrogen on any R₉heterocycle is included;

R₁₂ is morpholino, thiomorpholino, 1-oxothiomorpholino,1,1-dioxothiomorpholino, thiazolidin-3-yl, 1-oxothiazolidin-3-yl,1,1-dioxothiazolidin-3-yl, pyrrolidin-1-yl, piperidin-1-yl,piperazin-1-yl, piperazin-4-yl, azetidin-1-yl, 1,2-oxazinan-2-yl,pyrazolidin-1-yl, isoxazolidin-2-yl, isothiazolidin-2-yl,1,2-oxazetidin-2-yl, oxazolidin-3-yl, 3,4dihydroisoquinolin-2-yl,1,3-dihydrolsoindol-2-yl, 3,4-dihydro-2H-quinol-1-yl,2,3-dihydro-benzo[1,4]oxazin-4-yl, 2,3-dihydro-benzo[1,4]-thiazine-4-yl,3,4-dihydro-2H-quinoxalin-1-yl, 3,4-dihydro-benzo[c][1,2]oxazin-1-yl,1,4-dihydro-benzo[d][1,2]oxazin-3-yl,3,4-dihydro-benzo[e][1,2]-oxazin-2-yl, 3H-benzo[d]isoxazol-2-yl,3H-benzo[c]isoxazol-1-yl or azepan-1-yl,

wherein the R₁₂ rings are optionally mono-, di- or tri-substitutedindependently with halo, (C₁-C₅)alkyl, (C₁-C₅)alkoxy, hydroxy, amino,mono-N— or di-N,N—(C₁-C₅)alkylamino, formyl, carboxy, carbamoyl, mono-N—or di-N,N—(C₁-C₅)alkylcarbamoyl, (C₁-C₆)alkoxy(C₁-C₃)alkoxy,(C₁-C₅)alkoxycarbonyl, benzyloxycarbonyl,(C₁-C₅)alkoxycarbonyl(C₁C₅)alkyl, (C₁C₄)alkoxycarbonylamino,carboxy(C₁-C₅)alkyl, carbamoyl(C₁-C₅)alkyl, mono-N— ordi-N,N—(C₁-C₅)alkylcarbamoyl(C₁-C₅)alkyl, hydroxy(C₁-C₅)alkyl,(C₁-C₄)alkoxy(C₁₋₄)alkyl, amino(C₁C₄)alkyl, mono-N— ordi-N,N—(C₁-C₄)alkylamino(C₁-C₄)alkyl, oxo, hydroxylmino or(C₁-C₆)alkoxylmino and wherein no more than two substituents areselected from oxo, hydroxylmino or (C₁-C₆)alkoxylmino and oxo,hydroxylmino or (C₁-C₆)alkoxyimino are on nonaromatic carbon; and

the R₁₂ rings are optionally additionally mono- or di-substitutedindependently with (C₁-C₅)alkyl or halo;

or a pharmaceutically acceptable salt, ester, or ether thereof.

In some embodiments of formula (III), R₈ and R₉, together with thenitrogen to which they are bound, form an optionally fused, optionallysubstituted 5 or 6-membered heterocyclic ring, such as an optionallysubstituted piperazine ring (e.g., a 4-hydroxypiperazine ring).

In some embodiments of formula (III), when R₆ is (C₁-C₅)alkoxycarbonylor benzyloxycarbonyl then R₁ is 5-halo, 5-(C₁-C₄)alkyl or 5-cyano and R₄is (phenyl)(hydroxy)(C₁-C₄)alkyl, (phenyl)((C₁-C₄)alkoxy)(C₁-C₄)alkyl,hydroxymethyl or Ar(C₁-C₂)alkyl, wherein Ar is thien-2- or -3-yl, fur-2-or -3-yl or phenyl wherein the Ar is optionally mono- or di-substitutedindependently with halo; with the provisos that when R₄ is benzyl and R₅is methyl, R₁₂ is not 4-hydroxy-piperidin-1-yl or when R₄ is benzyl andR₅ is methyl R₆ is not C(O)N(CH₃)₂.

In some embodiments of formula (III), when R₁, R₁₀, and R₁₁ are H, R₄ isnot imidazol-4-ylmethyl, 2-phenylethyl or 2-hydroxy-2-phenylethyl.

In some embodiments of formula (III), when both R₈ and R₉ are n-pentyl,none of R₁ is 5-chloro, 5-bromo, 5-cyano, 5(C₁-C₅)alkyl, 5(C₁-C₅)alkoxyor trifluoromethyl.

In some embodiments of formula (III), when R₁₂ is3,4dihydroisoquinol-2-yl, the 3,4-dihydroisoquinol-2-yl is notsubstituted with carboxy((C₁-C₄)alkyl.

In some embodiments of formula (III), when R₈ is H and R₉ is(C₁-C₆)alkyl, R₉ is not substituted with carboxy or(C₁-C₄)alkoxycarbonyl on the carbon which is attached to the nitrogenatom N of NHR₉.

In some embodiments of formula (III), when R₆ is carboxy and R₁, R₁₀,R₁₁ and R₅ are all H, then R₄ is not benzyl, H, (phenyl)(hydroxy)methyl,methyl, ethyl or n-propyl.

Exemplary compounds of formula (III) are those belonging to a firstgroup of compounds in which:

R₁ is 5H, 5-halo, 5-methyl, 5-cyano or 5-trifluoromethyl;

R₁₀ and R₁₁ are each independently H or halo;

A is —C(H)═;

R₂ and R₃ are H;

R₄ is H, methyl, phenyl(C₁C₂)alkyl, wherein the phenyl groups are mono-or di-substituted independently with H, halo, (C₁-C₄)alkyl,(C₁C₄)alkoxy, trifluoromethyl, hydroxy, amino or cyano and wherein theR₄ groups are optionally additionally mono-substituted with halo; or

R₄ is thien-2- or -3-yl(C₁-C₂)alkyl, pyrid-2-, -3- or -4-yl(C₁-C₂)alkyl,thiazol-2-, -4- or -5-yl(C₁-C₂)alkyl, imidazol-2-, -4- or-5-yl(C₁-C₂)alkyl, fur-2- or -3-yl(C₁-C₂)alkyl, pyrrol-2- or-3-yl(C₁-C₂)alkyl, oxazol-2-, -4- or -5-yl(C₁-C₂)alkyl, pyrazol-3-, -4-or -5-yl(C₁-C₂)alkyl, isoxazol-3-, -4- or -5-yl(C₁-C₂)alkyl,isothiazol-3-, -4- or -5-yl(C₁-C₂)alkyl, pyridazin-3- or-4-yl(C₁-C₂)alkyl, pyrimidin-2-, -4-, -5- or -6-yl(C₁-C₂)alkyl,pyrazin-2- or -3-yl(C₁-C₂)alkyl or 1,3,5-triazin-2-yl(C₁-C₂)alkylwherein the preceding R₄ heterocycles are optionally mono- ordi-substituted independently with halo, trifluoromethyl, (C₁-C₄)alkyl,(C₁-C₄)alkoxy, amino or hydroxy and the mono- or di-substituents arebonded to cabin;

R₅ is H; and

R₆ is C(O)NR₈R₉ or C(O)R₁₂.

For example, compounds of formula (III) that may be used in conjunctionwith the compositions and methods described herein include those inwhich:

R₄ is H, phenyl(C₁-C₂)alkyl, thien-2- or -3-yl(C₁-C₂)alkyl, fur-2- or-3-yl(C₁-C₂)alkyl wherein the R₄ rings are mono- or di-substitutedindependently with H or fluoro;

R₆ is C(O)R₁₂; and

R₁₂ is morpholino, thiomorpholino, 1-oxothiomorpholino,1,1-dioxothiomorpholino, thiazolidin-3-yl, 1-oxothiazolidin-3-yl,1,1-dioxothiazolidin-3-yl, pyrrolidin-1-yl, piperidin-1-yl,piperazin-1-yl, piperazin-4-yl, azetidin-1-yl, 1,2oxazinan-2-yl,isoxazolidin-2-yl, isothiazolidin-2-yl, 1,2-oxazetidin-2-yl,oxazolidin-3-yl, 1,3-dihydroisoindol-2-yl, or azepan-1-yl,

the R₁₂ rings are optionally mono- or di-substituted independently withhalo, (C₁-C₅)alkyl, (C₁-C₅)alkoxy, hydroxy, amino, mono-N— ordi-N,N—(C₁-C₅)alkylamino, formyl, carboxy, carbamoyl, mono-N— ordi-N,N—(C₁-C₅)alkylcarbamoyl, (C₁-C₅)alkoxycarbonyl,hydroxy(C₁-C₅)alkyl, amino(C₁-C₄)alkyl, mono-N— ordi-N,N—(C₁C₄)alkylamino(C₁-C₄)alkyl, oxo, hydroxylmino or(C₁-C₆)alkoxylmino with the proviso that only the R₁₂ heterocyclesthiazolidin-3-yl, pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl,piperazin-4-yl, azetidin-1-yl, 1,2-oxazinan-2-yl, isoxazolidin-2-yl, oroxazolidin-3-yl are optionally mono- or di-substituted with oxo,hydroxylmino, or (C₁-C₆)alkoxylmino; and

the R₁₂ rings are optionally additionally mono- or di-substitutedindependently with (C₁-C₅)alkyl.

Further exemplary compounds of formula (III) that may be used inconjunction with the compositions and methods described herein include:5-Chloro-1H-indole-2-carboxylic acid[(1S)-benzyl-2-(3-hydroxylmino-pyrrolidin-1-yl)-2-oxo-ethyl]-amide,5-Chloro-1H-indole-2-carboxylic acid[2-(cis-3,4-dihydroxy-pyrrolidin-1-yl)-2-oxo-ethyl]-amide,5-Chloro-1H-indole-2-carboxylic acid[2-((3S,4S)-dihydroxy-pyrrolidin-1-yl)-2-oxo-ethyl]-amide,5-Chloro-1H-indole-2-carboxylic acid[(1S)-benzyl-2-(cis-3,4-dihydroxy-pyrrolidin-1-yl)-2-oxo-ethyl]-amide,5-Chloro-1H-indole-2-carboxylic acid[2-(1,1-dioxo-thiazoildin-3-yl)-2-oxo-ethyl]-amide,5-Chloro-1H-indole-2-carboxylic acid(2-oxo-2-thiazolidin-3-yl-ethyl)-amide, 5-Chloro-1H-indole-2-carboxylicacid[(1S)-(4-fluoro-benzyl)-2-(4-hydroxy-piperidin-1-yl)-2-oxo-ethyl]-amide,5-Chloro-1H-indole-2-carboxylic acid[(1S)-benzyl-2-((3RS)-hydroxy-piperidin-1-yl)-2-oxo-ethyl]-amide,5Chloro-1H-indole-2-carboxylic acid[2-oxo-2-((1RS)-oxo-1-thiazolidin-3-yl)-ethyl]-amide,5-Chloro-1H-indole-2-carboxylic acid[(1S)-(2-fluoro-benzyl)-2-(4-hydroxy-piperidin-1-yl)-2-oxo-ethyl]-amide,5-Chloro-1H-indole-2-carboxylic acid[(1S)-benzyl-2-((3S,4S)-dihydroxy-pyrrolidin-1-yl)-2-oxo-ethyl]-amide,5-Chloro-1H-indole-2-carboxylic acid[(1S)-benzyl-2-(3-hydroxy-azetidin-1-yl)-2-oxo-ethyl]-amide,5-Chloro-1H-indole-2-carboxylic acid[(1S)-benzyl-2-(3-hydroxyimino-azetidin-1-yl)-2-oxo-ethyl]-amide, and5-Chloro-1H-indole-2-carboxylic acid[(1S)-benzyl-2-(4-hydroxyimino-piperidin-1-yl)-2-oxo-ethyl]-amide.

Further exemplary compounds of formula (III) that may be used inconjunction with the compositions and methods described herein includethose in which:

R₄ is H; and

R₁₂ is thiazolidin-3-yl, 1-oxo-thiazolidin-3-yl,1,1-dioxo-thiazolidin-3-yl or oxazolidin-3-yl or the R₁₂ substituentsoptionally mono- or di-substituted independently with carboxy,(C₁-C₅)alkoxycarbonyl, hydroxy(C₁-C₃)alkyl, amino(C₁-C₃)alkyl, mono-N—or di-N,N—(C₁-C₃)alkylamino(C₁-C₃)alkyl or

R₁₂ is mono- or di-substituted pyrrolidin-1-yl wherein the substituentsare independently carboxy, (C₁-C₅)alkoxycarbonyl, (C₁-C₅)alkoxy,hydroxy, hydroxy(C₁-C₃)alkyl, amino, amino(C₁-C₃)alkyl, mono-N— ordi-N,N—(C₁-C₃)alkylamino(C₁-C₃)alkyl or mono-N— ordi-N,N—(C₁-C₄)alkylamino; and the R₁₂ rings are optionally additionally,independently, disubstituted with (C₁-C₅)alkyl.

Further exemplary compounds of formula (III) that may be used inconjunction with the compositions and methods described herein includethose in which:

(a) R₁ is 5-chloro;

R₁₀ and R₁₁ are H; and

R₁₂ is cis-3,4-dihydroxy-pyrrolidin-1-yl;

(b) R₁ is 5-chloro;

R₁₀ and R₁₁ are H; and

R₁₂ is (3S,4S)-dihydroxy-pyrrolidin-1-yl;

(c) R₁ is 5-chloro;

R₁₀ and R₁₁ are H; and

R₁₂ is 1,1-dioxo-thiazolidin-3-yl;

(d) R₁ is 5-chloro;

R₁₀ and R₁₁ are H; and

R₁₂ is thiazolidin-3-yl; and

(e) R₁ is 5-chloro;

R₁₀ and R₁₁ are H; and

R₁₂ is 1-oxo-thiazolidin-3-yl.

Further exemplary compounds of formula (III) that may be used inconjunction with the compositions and methods described herein includethose in which:

R₄ is phenylmethyl, thien-2- or -3-ylmethyl wherein the R₄ rings areoptionally mono- or di-substituted with fluoro; and

R₁₂ is thiazolidin-3-yl, 1-oxo-thiazolidin-3-yl,1,1-dioxo-thiazolidin-3-yl or oxazolidin-3-yl or the R₁₂ substituentsoptionally mono- or di-substituted independently with carboxy or(C₁-C₅)alkoxycarbonyl, hydroxy(C₁-C₃)alkyl, amino(C₁-C₃)alkyl or mono-N—or di-N,N—(C₁-C₃)alkylamino(C₁-C₃)alkyl or

R₁₂ is mono- or di-substituted azetidin-1-yl or mono- or di-substitutedpyrrolidin-1-yl or mono- or di-substituted piperidin-1-yl wherein thesubstituents are independently carboxy, (C₁-C₅)alkoxycarbonyl,hydroxy(C₁-C₃)alkyl, amino(C₁-C₃)alkyl, mono-N— ordi-N,N—(C₁-C₃)alkylamino(C₁-C₃)alkyl, hydroxy, (C₁-C₅)alkoxy, amino,mono-N— or di-N,N—(C₁-C₅)alkylamino, oxo, hydroxylmino or(C₁-C₅)alkoxylmino; and

the R₁₂ rings are optionally additionally mono- or di-substitutedindependently with (C₁-C₅)alkyl.

Further exemplary compounds of formula (III) that may be used inconjunction with the compositions and methods described herein includethose in which:

(a) R₁ is 5-chloro;

R₁₀ and R₁₁ are H;

R₄ is 4-fluorobenzyl;

R₁₂ is 4-hydroxypiperidin-1-yl; and

the stereochemistry of carbon (a) is (S);

(b) R₁ is 5-chloro;

R₁₀ and R₁₁ are H;

R₄ is benzyl;

R₁₂ is 3-hydroxypiperidin-1-yl; and

the stereochemistry of carbon (a) is (S);

(c) R₁ is 5-chloro;

R₁₀ and R₁₁ are H;

R₄ is benzyl;

R₁₂ is cis-3,4-dihydroxy-pyrrolidin-1-yl; and

the stereochemistry of carbon (a) is S;

(d) R₁ is 5-chloro;

R₁₀ and R₁₁ are H; R₄ is benzyl;

R₁₂ is 3-hydroxyimino-pyrrolidin-1-yl; and

the stereochemistry of carbon (a) is (S);

(e) R₁ is 5-chloro;

R₁₀ and R₁₁ are H;

R₄ is 2-fluorobenzyl;

R₁₂ is 4-hydroxypiperidin-1-yl; and

the stereochemistry of carbon (a) is (S);

(f) R₁ is 5-chloro;

R₁₀ and R₁₁ are H;

R₄ is benzyl;

R₁₂ is (3S,4S)-dihydroxy-pyrrolidin-1-yl; and

the stereochemistry of carbon (a) is (S);

(g) R₁ is 5-chloro;

R₁₀ and R₁₁ are H;

R₄ is benzyl;

R₁₂ is 3-hydroxy-azetidin-1-yl; and

the stereochemistry of carbon (a) is (S);

(h) R₁ is 5-chloro;

R₁₀ and R₁₁ are H;

R₄ is benzyl;

R₁₂ is 3-hydroxyimino-azetidin-1-yl; and

the stereochemistry of carbon (a) is (S); and

(i) R₁ is 5chloro;

R₁₀ and R₁₁ are H;

R₄ is benzyl;

R₁₂ is 4-hydroxyimino-piperidin-1-yl; and

the stereochemistry of carbon (a) is (S).

Additionally, exemplary compounds of formula (III) are those belongingto a second group of compounds in which:

R₄ is H, phenyl(C₁-C₂)alkyl, thien-2- or -3-yl(C₁-C₂)alkyl, fur-2- or-3-yl(C₁-C₂)alkyl wherein the R₄ rings are mono- or di-substitutedindependently with H or fluoro;

R₆ is C(O)NR₈R₉; and

R₈ is H, (C₁-C₅)alkyl, hydroxy or (C₁-C₄)alkoxy; and

R₉ is H, cyclo(C₄-C₆)alkyl, cyclo(C₃-C₆)alkyl(C₁-C₅)alkyl,methylene-perfluorinated(C₁-C₃)alkyl, pyridyl, pyrrolidinyl, oxazolyl,thiazolyl, imidazolyl, piperidinyl, benzothiazolyl or thiochromanyl; or

R₉ is (C₁-C₅)alkyl wherein the (C₁-C₅)alkyl is optionally substitutedwith cyclo(C₄-C₆)alkenyl, phenyl, thienyl, pyridyl, pyrrolidinyl,oxazolyl, thiazolyl, imidazolyl, pyrazolyl, piperidinyl, morpholinyl,thiomorpholinyl, 1-oxothiomorpholinyl, or 1,1-dioxothiomorpholinyl andwherein the (C₁-C₅)alkyl or (C₁-C₄)alkoxy is optionally additionallyindependently mono- or di-substituted with halo, hydroxy, (C₁—C₅)alkoxy,amino, mono-N— or di-N,N—(C₁-C₅)alkylamino, cyano, carboxy, or(C₁-C₄)alkoxycarbonyl; wherein the R₉ rings are optionally mono- ordi-substituted independently on carbon with halo, (C₁-C₄)alkyl,(C₁-C₄)alkoxy, hydroxy, amino, mono-N— or di-N,N—(C₁-C₄)alkylamino,carbamoyl, (C₁-C₅)alkoxycarbonyl or carbamoyl.

Further exemplary compounds of formula (III) that may be used inconjunction with the compositions and methods described herein includethose in which:

(a) R₁ is 5-chloro;

R₁₀ and R₁₁ are H;

R₄ is benzyl;

R₈ is methyl; and

R₉ is 3-(dimethylamino)propyl;

(b) the stereochemistry of carbon (a) is (S);

R₁ is 5-chloro;

R₁₀ and R₁₁ are H;

R₄ is benzyl;

R₈ is methyl; and

R₉ is 3-pyridyl;

(c) the stereochemistry of carbon (a) is (S);

R₁ is 5-chloro;

R₁₀ and R₁₁ are H;

R₄ is benzyl;

R₈ is methyl; and

R₉ is 2-hydroxyethyl; and

(d) the stereochemistry of carbon (a) is (S);

R₁ is 5-fluoro;

R₁₀ and R₁₁ are H;

R₄ is 4-fluorophenylmethyl;

R₈ is methyl; and

R₉ is 2-morpholinoethyl.

Additionally, exemplary compounds of formula (III) are those belongingto a third group of compounds in which:

R₄ is H, phenyl(C₁-C₂)alkyl, thien-2- or -3-yl(C₁-C₂)alkyl, fur-2- or-3-yl(C₁-C₂)alkyl wherein the R₄ rings are mono- or di-substitutedindependently with H or fluoro;

R₆ is C(O)NR₈R₉; and

R₈ is H, (C₁-C₅)alkyl, hydroxy or (C₁-C₄)alkoxy; and

R₉ is (C₁-C₄)alkoxy wherein the (C₁-C₄)alkoxy is optionally substitutedwith cyclo(C₄-C₆)alkenyl, phenyl, thienyl, pyridyl, pyrrolidinyl,oxazolyl, thiazolyl, imidazolyl, pyrazolyl, piperidinyl, morpholinyl,thiomorpholinyl, 1-oxothiomorpholinyl, or 1,1-dioxothiomorpholinyl andwherein the (C₁-C₅)alkyl or (C₁-C₄)alkoxy is optionally additionallyindependently mono- or di-substituted with halo, hydroxy, (C₁-C₅)alkoxy,amino, mono-N— or di-N,N—(C₁-C₅)alkylamino, cyano, carboxy, or(C₁-C₄)alkoxycarbonyl; wherein the R₉ rings are optionally mono- ordi-substituted independently on carbon with halo, (C₁-C₄)alkyl,(C₁-C₄)alkoxy, hydroxy, amino, mono-N— or di-N,N—(C₁-C₄)alkylamino,carbamoyl, (C₁-C₅)alkoxycarbonyl or carbamoyl.

Further exemplary compounds of formula (III) that may be used inconjunction with the compositions and methods described herein includethose in which:

(a) R₁ is 5-chloro;

R₁₀ and R₁₁ are H;

R₄ is benzyl;

R₈ is methyl; and

R₉ is 2-hydroxyethoxy;

(b) the stereochemistry of carbon (a) is (S);

R₁ is 5-chloro;

R₁₀ and R₁₁ are H;

R₄ is 4-fluorophenylmethyl;

R₈ is methyl; and

R₉ is methoxy;

(c) the stereochemistry of carbon (a) is (S);

R₁ is 5-chloro;

R₁₀ and R₁₁ are H;

R₄ is benzyl;

R₈ is methyl; and

R₉ is methoxy;

Further exemplary compounds of formula (III) that may be used inconjunction with the compositions and methods described herein includethose in which:

R₁ is 5-halo, 5-methyl, 5-cyano or trifluoromethyl;

R₁₀ and R₁₁ are each independently H or halo;

A is —C(H)═;

R₂ and R₃ are H;

R₄ is H, phenyl(C₁-C₂)alkyl, thien-2- or -3-yl(C₁-C₂)alkyl, fur-2- or3-yl(C₁-C₂)alkyl wherein the rings are mono- or di-substitutedIndependently with H or fluoro;

R₅ is H; and

R₆ is (C₁-C₅)alkoxycarbonyl.

Further exemplary compounds of formula (III) that may be used inconjunction with the compositions and methods described herein includethose in which:

R₁ is 5-halo, 5-methyl, 5-cyano or trifluoromethyl;

R₁₀ and R₁₁ are each independently H or halo;

A is —C(H)═;

R₂ and R₃ are H;

R₄ is H, methyl or phenyl(C₁-C₂)alkyl, wherein the phenyl groups aremono- or di-substituted independently with H, halo, (C₁-C₄)alkyl,(C₁-C₄)alkoxy, trifluoromethyl, hydroxy, amino or cyano and wherein thephenyl groups are additionally mono- or di-substituted independently Hor halo; or

R₄ is thien-2- or -3yl(C₁-C₂)alkyl, pyrid-2-, -3- or -4-yl(C₁-C₂)alkyl,thiazol-2-, -4- or -5-yl(C₁-C₂)alkyl, imidazol-2-, -4- or-5-yl(C₁-C₂)alkyl, fur-2- or -3-yl(C₁-C₂)alkyl, pyrrol-2- or-3-yl(C₁-C₂)alkyl, oxazol-2-, -4- or -5-yl(C₁-C₂)alkyl, pyrazol-3-, -4-or -5-yl(C₁-C₂)alkyl, isoxazol-3-, -4- or -5-yl(C₁-C₂)alkyl,isothiazol-3-, -4- or -5-yl(C₁-C₂)alkyl, pyridazin-3- or-4yl(C₁-C₂)alkyl, pyrimidin-2-, -4-, -5- or -6-yl(C₁-C₂)alkyl,pyrazin-2- or -3-yl(C₁-C₂)alkyl or 1,3,5-triazin-2-yl(C₁-C₂)alkylwherein the preceding R₄ heterocycles are optionally mono- ordi-substituted independently with halo, trifluoromethyl, (C₁-C₄)alkyl,(C₁-C₄)alkoxy, amino or hydroxy and the mono- or di-substituents arebonded to carbon;

R₅ is H; and

R₆ is carboxy.

Further exemplary compounds of formula (III) that may be used inconjunction with the compositions and methods described herein includethose in which:

R₁₀ and R₁₁ are H; and

R₄ is H.

Further exemplary compounds of formula (III) that may be used inconjunction with the compositions and methods described herein includethose in which R₁ is 5-chloro.

In some embodiments, the CYP51A1 inhibitor is a compound represented byformula (IV)

wherein Ar is thienyl, pyridyl, biphenyl, phenyl or phenyl substitutedby one or more of halo, nitro, cyano, lower alkyl, lower alkoxy orperhalo(lower)alkyl;

Y is CH or N;

either one of A, B and C is oxygen and the remaining two of A, B and Care CH₂; or A is oxygen, B is CH₂, and C is a direct bond;

Q is:

W is —NR₅—, —O—, or —S(O)_(n)—;

X is —NO₂, —P—NR₆R₇,

Ar, OR₃ or halogen;

P is a direct bond, —CHR₁₁— or —CHR₁₁CHR₁₂—;

R₁, R₈, R₉ and R₁₀ are independently hydrogen, lower alkyl or loweralkyl substituted by one or more hydroxy groups;

R₂, R₄, R₁₁, R₁₂ and R₁₄ are hydrogen, hydroxy, lower alkyl or loweralkyl substituted by one or more hydroxy groups;

R₃ and R₁₃ are independently hydrogen, lower alkyl, (C₂-C₈)perhaloalkanoyl or (C₂-C₈) alkanoyl;

R₆ and R₇ are independently hydrogen, lower alkyl, phenyl or phenylsubstituted by one or more of halo, perhalo(lower)alkyl,(C₂-C₈)alkanoyl, lower alkyl, lower alkyl substituted by one or morehydroxy groups, lower alkoxy, or2-(lower)alkyl-3-oxo-1,2,4-triazol-4-yl, or R₆ and R₇ taken togetherwith the nitrogen atom in NR₆ R₇ form unsubstituted or substituted 5- or6-membered heterocyclyl ring systems containing carbon and one to fourheteroatoms chosen from N, O and S, the heterocyclyl substituents being(C₁-C₈)alkanoyl, lower alkyl, lower alkoxycarbonyl, aminocarbonyl,N-lower alkylaminocarbonyl, N,N-di(lower alkyl)amino carbonyl,aminothiocarbonyl, N-lower alkylaminothiocarbonyl, N,N-di(loweralkyl)aminothiocarbonyl, lower alkyl sulfonyl, phenyl-substituted loweralkyl sulfonyl, N-lower alkylamino, N,N-di(lower alkyl)amino,1,3-imidazol-1-yl, 2-loweralkylsulfenyl-1,3-imidazol-1-yl, 2-pyridinyl,2-thiazolyl, 2-lower alkyl-3-oxo-1,2,4-triazol-4-yl, 1-loweralkylbenzimidazol-2-yl, phenyl or phenyl substituted by one or more ofhalo, perhalo lower alkyl, (C₂-C₈) alkanoyl, lower alkyl, lower alkylsubstituted by one or more hydroxy group, lower alkoxy,1H,2,4-triazol-1-yl, 2-lower alkyl-3-oxo-1,2,4-triazol-4-yl, or asubstituent represented by the formula:

R₅ is a lower alkyl, lower alkoxy, amino, N,N-dilower alkylamino, phenylor phenyl substituted by one or more of halo, perhalo lower alkyl, loweralkoxy, nitro, cyano, (C₂-C₈)alkanoyl;

p is 0, 1, 2, 3, 4 or 5;

n is 0, 1 or 2;

r is 1 or 2; and

t is 0, 1, 2 or 3;

or a pharmaceutically acceptable salt, ester, or ether thereof.

In some embodiments of formula (IV), when R₂, R₁₁, or R₁₂ is attached toa carbon atom adjacent to —NR₅, —S(O)_(n) or —O—, the R₂, R₁₁, or R₁₂ isnot hydroxy.

In some embodiments, the CYP51A1 inhibitor is a compound represented byformula (V)

wherein Y and Ar are as defined for formula (IV) herein;

one of A, B or C is oxygen and the remaining two of A, B, or C are—CH₂—;

T is ═O, ═NOR₁, ═NNR₁R₂ or

wherein R₁ is hydrogen, lower alkyl or lower alkyl substituted by one ormore hydroxy groups; and

R₂ is hydrogen, hydroxy, lower alkyl or lower alkyl substituted by oneor more hydroxy groups;

or a pharmaceutically acceptable salt, ester, or ether thereof.

In some embodiments, the CYP51A1 inhibitor is a compound represented byformula (VI)

wherein Y, Ar, R₁, R₂, R₆ and R₇ are as previously defined for formula(IV) herein, and either one of A, B and C is oxygen and the remainingtwo of A, B and C are CH₂, or A is oxygen, B is CH₂, and C is a directbond;

or a pharmaceutically acceptable salt, ester, or ether thereof.

Exemplary compound of formula (VI) for use in conjunction with thecompositions and methods described herein are those in which NR₆ R₇ formunsubstituted or substituted 5- or 6-membered heterocyclyl ring systemscontaining carbon and one to four heteroatoms chosen from N, O and S,the heterocyclyl substituents being (C₁-C₈) alkanoyl, lower alkyl, loweralkoxycarbonyl, aminocarbonyl, N-lower alkylaminocarbonyl, N,N-di(loweralkyl)aminocarbonyl, aminothiocarbonyl, N-lower alkylaminothiocarbonyl,N,N-di(lower alkyl)aminothiocarbonyl, lower alkyl sulfonyl,phenyl-substituted lower alkyl sulfonyl, N-lower alkyl-amino,N,N-di(lower alkyl)amino, 1,3-imidazol-1-yl,2-loweralkylsulfenyl-1,3-imidazol-1-yl, 2-pyridinyl, 2-thiazolyl,2-lower alkyl-3-oxo-1,2,4-triazol-4-yl, 1-lower alkylbenzimidazol-2-yl,phenyl, phenyl substituted by one or more of halo, perhalo lower alkyl,(C₂-C₈)alkanoyl, lower alkyl, lower alkyl substituted by one or morehydroxy groups, lower alkoxy, 1H,2,4-triazol-1-yl or 2-loweralkyl-3-oxo-1,2,4-triazol-4-yl; R₅ is a lower alkyl, amino, N,N-diloweralkylamino, or

In some embodiments of formula (VI), the NR₆R₇ is:

wherein Z is hydrogen, (C₁-C₈) alkanoyl, lower alkyl, (C₁-C₈)perhaloalkanoyl or phenyl substituted by2-loweralkyl-3-oxo-1,2,4-triazol-4-yl.

In some embodiments, the CYP51A1 inhibitor is a compound represented byformula (VII)

wherein one of A, B and C is oxygen and the remaining two of A, B and Care —CH₂—, or two of A, B and C are —CH₂—;

each Hal is independently a halogen, such as Cl or F; and

Z is lower alkyl, (C₂-C₈)alkanoyl, or optionally substituted phenyl,such as phenyl substituted by 2-loweralkyl-3-oxo-1,2,4triazol-4-yl;

or a pharmaceutically acceptable salt, ester, or ether thereof.

In some embodiments of formula (VII), the compound is selected from:

or a pharmaceutically acceptable salt, ester, or ether thereof.

In some embodiments, the CYP51A1 inhibitor is a compound represented byformula (VIII)

wherein Ar is thienyl, pyridyl, biphenyl, phenyl, or phenyl substitutedby one or more of halo, nitro, cyano, lower alkyl, lower alkoxy orperhalo(lower)alkyl;

Q is:

W is —NR₅—, —O—, or —S(O)_(n)—;

X is —NO₂, —P—NR₆R₇,

Ar, OR₃ or halogen;

P is a direct bond, —CHR₁₁— or —CHR₁₁CHR₁₂—;

R₈, R₉ and R₁₀ are independently hydrogen, lower alkyl or lower alkylsubstituted by one or more hydroxy groups;

R₄, R₁₁, R₁₂ and R₁₄ are hydrogen, hydroxy, lower alkyl or lower alkylsubstituted by one or more hydroxy groups;

R₃ and R₁₃ are independently hydrogen, lower alkyl, (C₂-C₈)perhaloalkanoyl or (C₂-C₈) alkanoyl;

R₆ and R₇ are independently hydrogen, lower alkyl, phenyl or phenylsubstituted by one or more of halo, perhalo(lower)alkyl,(C₂-C₈)alkanoyl, lower alkyl, lower alkyl substituted by one or morehydroxy groups, lower alkoxy, or2-(lower)alkyl-3-oxo-1,2,4-triazol-4-yl, or R₆ and R₇ taken togetherwith the nitrogen atom in NR₆ R₇ form unsubstituted or substituted 5- or6-membered heterocyclyl ring systems containing carbon and one to fourheteroatoms chosen from N, O and S, the heterocyclyl substituents being(C₁-C₈)alkanoyl, lower alkyl, lower alkoxycarbonyl, aminocarbonyl,N-lower alkylaminocarbonyl, N,N-di(lower alkyl)amino carbonyl,aminothiocarbonyl, N-lower alkylaminothiocarbonyl, N,N-di(loweralkyl)aminothiocarbonyl, lower alkyl sulfonyl, phenyl-substituted loweralkyl sulfonyl, N-lower alkylamino, N,N-di(lower alkyl)amino,1,3-imidazol-1-yl, 2-loweralkylsulfenyl-1,3-imidazol-1-yl, 2-pyridinyl,2-thiazolyl, 2-lower alkyl-3-oxo-1,2,4-triazol-4-yl, 1-loweralkylbenzimidazol-2-yl, phenyl or phenyl substituted by one or more ofhalo, perhalo lower alkyl, (C₂-C₈) alkanoyl, lower alkyl, lower alkylsubstituted by one or more hydroxy group, lower alkoxy,1H,2,4-triazol-1-yl, 2-lower alkyl-3-oxo-1,2,4-triazol-4-yl, or asubstituent represented by the formula:

R₅ is a lower alkyl, lower alkoxy, amino, N,N-dilower alkylamino, phenylor phenyl substituted by one or more of halo, perhalo lower alkyl, loweralkoxy, nitro, cyano, (C₂-C₈)alkanoyl;

p is 0, 1, 2, 3, 4 or 5;

n is 0, 1 or 2;

r is 1 or 2; and

t is 0, 1, 2 or 3;

R₁ is hydrogen, lower alkyl or lower alkyl substituted by one or morehydroxy groups; and

R₂ is hydrogen, hydroxy, lower alkyl or lower alkyl substituted by oneor more hydroxy groups;

or a pharmaceutically acceptable salt, ester, or ether thereof.

In some embodiments, the CYP51A1 inhibitor is a compound represented byformula (IX)

wherein each X is independently a halogen, such as F or Cl; and

R₁ is a straight or branched chain (C₃ to C₈) alkyl group optionallysubstituted by one or two hydroxy moieties or by one or two groupsconvertible in vivo into hydroxy moieties;

or a pharmaceutically acceptable salt, ester, or ether thereof.

In some embodiments of formula (IX), the compound is represented byformula (X)

wherein each X is independently a halogen, such as F or Cl; and

R₂ is H or (C₁-C₃) alkyl and R₃ is (C₁-C₃) alkyl optionally substitutedby one hydroxy moiety or by a group convertible in vivo into a hydroxymoiety;

or a pharmaceutically acceptable salt, ester, or ether thereof.

In some embodiments of formula (X), the compound is represented byformula (XI)

wherein R₅ is:

or a pharmaceutically acceptable salt, ester, or ether thereof.

In some embodiments of formula (XI), the compound is represented byformula (XII)

wherein R₉ is —H(C₂H₅)CH(R₆)CH₃ or —H(CH₃)CH(R₆)CH₃;

R₆ is OH or a group convertible in vivo into OH;

or a pharmaceutically acceptable salt, ester, or ether thereof.

In some embodiments of formula (XII), the compound is:

or a pharmaceutically acceptable salt, ester, or ether thereof.

In some embodiments of formulas (IX)-(XII), the compound is an ester ofthe corresponding structural formula, such as a phosphate ester. Thephosphate ester may be, for example, a phosphate ester selected from

wherein z is 0 or 1, R₇ is a (C₁-C₆) straight or branched chain alkylgroup or H, f and n are independently an integer from 0 to 6, m is zeroor 1 and W is H, CH₂ Ar or and Ar is phenyl, phenyl substituted by halo,nitro, cyano or trihalomethyl.

In some embodiments, the CYP51A1 inhibitor is a compound represented byformula (XIII)

wherein R_(O) is alkyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 6carbon atoms, cycloalkyl-alkyl in which the cycloalkyl is of 3 to 6carbon atoms and the alkyl portion of 1 to 3 carbon atoms, thecycloalkyl and cycloalkyl-alkyl being optionally ring substituted by oneor two alkyl groups of 1 to 3 carbon atoms;

R is hydrogen, fluoro, chloro, bromo, alkyl of 1 to 4 carbon atoms,alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms ornitro;

R′ is hydrogen, fluoro, chloro, bromo, alkyl of 1 to 4 carbon atoms,alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, —CF₃ inthe 3-position of Ring A, nitro, —CN, —COOR″, an optionally substitutedphenyl group of the formula:

or an optionally substituted phenoxy group in the 4-position of Ring Aand having the formula:

R″ is hydrogen, alkyl of 1 to 4 carbon atoms or a cation, preferably anagriculturally acceptable cation, or R and R′ together representalkylenedioxy of 1 or 2 carbon atoms substituted onto adjacent carbonatoms of the phenyl Ring A; and

Y_(O) and Y are independently hydrogen, fluoro, chloro, bromo, alkyl of1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms;

or a pharmaceutically acceptable salt, ester, or ether thereof.

In some embodiments of formula (XIII), when R_(O) is n-butyl: (a) atleast one of R and R′ is other than hydrogen and (b) R and R′ are notboth halo.

In some embodiments, the CYP51A1 inhibitor is anα-[aryl(alkylene)_(m)]-α-[CR₁R₂—(CHR₃)_(n)-R₄]1H-1,2,4-triazole-1-ethanol(formula (XIV-A)) or anα-[aryl(alkylene)_(m)]-α-[CR₁R₂—(CHR₃)_(n)—R₄]1H-imidazole-1-ethanol(formula (XIV-B)), or a pharmaceutically acceptable salt, ester, orether thereof, wherein:

R₁ is C₁₋₅ alkyl, unsubstituted or substituted by halogen, byC₁₋₅-alkoxy, by phenyl-C₁₋₃ alkoxy, by phenoxy, by C₁₋₅ alkylthio, byphenyl-C₁₋₃ alkylthio or by phenylthio, whereby optional phenyl groupsmay be substituted by C₁₋₅ alkyl, halogen, halogen substituted C₁₋₅alkyl, C₁₋₅ alkoxy or halogen substituted C₁₋₅ alkoxy; or

is C₂₋₅ alkenyl or C₂₋₅ alkynyl, unsubstituted or substituted byhalogen; or

is cycloalkyl, unsubstituted or substituted by C₁₋₅ alkyl; or

is phenyl, unsubstituted or substituted by substituents selected fromthe group consisting of halogen and C₁₋₅ alkyl;

R₂ and R₃, independently, are H or have an R₁ significance, whereby R₁and R₂ may be linked together to form a C₃₋₇ cycloalkyl group;

m is 0 or 1;

n is 0, 1 or 2; and

R₄ is C₃₋₇ cycloalkyl, unsubstituted or substituted by C₁₋₅ alkyl.

The aryl portion in the α-[aryl(alkylen)_(m)] moiety of formula (XIV-A)or (XIV-B) (collectively “formula (XIV)”) may be an aromatic hydrocarbon(e.g. naphthyl, preferably phenyl) unsubstituted or substituted, or aheteroaromatic ring linked by one of its ring carbon atoms (e.g. a 5- or6-membered ring with 1 or 2 heteroatoms from the group O, N and S,preferably furyl, thienyl or pyridyl), and may be unsubstituted orsubstituted.

Examples of suitable α-[aryl(alkylene)_(m)] groups that may be presentin formula (XIV) are phenyl, benzyl and α-C₁₋₅ alkylbenzyl (e.g.,unsubstituted, mono- or multiple-substituted in the phenyl moiety byNO₂, halogen, C₁₋₅ alkyl, C₂₋₅ alkenyl, C₂₋₅ alkynyl, or C₁₋₅ alkoxy(unsubstituted or halogenated), phenyl, or phenoxy, unsubstituted orsubstituted). Further examples of suitable α-aryl groups are theheteroaromatic 3-pyridyl group and 2-thienyl and 2-furyl, which may be,for example, unsubstituted or singly substituted by halogen or loweralkyl (e.g. 5-Cl-2-thienyl and 5-tert.butyl-2-furyl).

For example, the α-[aryl(alkylene)_(m)] group may be phenyl, benzyl, orα-C₁₋₅ alkylbenzyl substituted in the phenyl moiety by R₅, R₆ and/or R₇,wherein:

R₅ and R₆, independently, are H; halogen, C₁₋₅ alkyl, C₂₋₅ alkenyl, C₂₋₅alkynyl, or C₁₋₅ alkoxy, (e.g., unsubstituted or halogenated), phenyl orphenoxy (e.g., unsubstituted or substituted), or NO₂; and

R₇ is H, C₁₋₅ alkyl or halogen.

In some embodiments, the compound represented by formula (XIV) is acompound represented by formula (XV)

wherein R₁, R₂, R₃, R₄, R₅, R₆, R₇, m and n are as defined for formula(XIV) herein, R₈ is H or C₁₋₅ alkyl, and Y is CH or N;

or a pharmaceutically acceptable salt, ester, or ether thereof.

In some embodiments, the compound represented by formula (XV) is acompound represented by formula (XVI)

wherein R₂ is hydrogen or optionally substituted alkyl, such asoptionally substituted lower alkyl (e.g., methyl, ethyl, n-propyl,iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl,n-hexyl, or the like); and

R₅ and R₆ are each independently hydrogen or a halogen atom, such aschloro;

or a pharmaceutically acceptable salt, ester, or ether thereof.

In some embodiments, the CYP51A1 inhibitor is2-(4-chlorophenyl)-3-cyclopropyl-1-(1H-1,2,4-triazol-1-yl)-butan-2-ol,2-(4-chlorophenyl)-3-cyclopropyl-3-methyl-1-(1H-1,2,4-triazol-1-yl)-butan-2-ol,2-(2,4-diclorophenyl)-3-cyclopropyl-1-(1H-1,2,4-triazol-1-yl)butan-2-ol, or2-(2,4-dichlorophenyl-3-cyclopropyl-3-methyl-1-(1H-1,2,4-triazol-1-yl)butan-2-ol.

In some embodiments, the CYP51A1 inhibitor is a compound represented byformula (XVII)

wherein R is phenyl optionally substituted by 1 to 3 substituents eachindependently selected from halo and CF₃;

R¹ is C₁-C₄ alkyl;

R₂ is H or C₁-C₄ alkyl; and

“Het”, which is attached to the adjacent carbon atom by a ring carbonatom, is selected from pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyland triazinyl. “Het” may be optionally substituted by C₁-C₄ alkyl, C₁-C₄alkoxy, halo, CF₃, CN, NO₂, NH₂, —NH(C₁-C₄ alkanoyl) or —NHCO₂ (C₁-C₄alkyl);

or a pharmaceutically acceptable salt, ester, or ether thereof.

In some embodiments of formula (XVII), “Het” is selected from 2- and4-pyridinyl, pyridazinyl, 2- and 4-pyrimidinyl, pyrazinyl and triazinyl,and may be optionally substituted by C₁-C₄ alkyl, C₁-C₄ alkoxy, halo,CF₃, CN, NO₂, NH₂, —NH(C₁-C₄ alkanoyl) or —NHCO₂ (C₁-C₄ alkyl). In someembodiments, “Het” is pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl ortriazinyl, and may be optionally substituted by C₁-C₄ alkyl, C₁-C₄alkoxy, halo, CF₃, NO₂, NH₂ or —NH(C₁-C₄ alkanoyl).

In some embodiments of formula (XVII), R is a substituted phenyl moiety,such as 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-iodophenyl,2-trifluoromethylphenyl, 2,4-dichlorophenyl, 2,4-difluorophenyl,2-chloro-4-fluorophenyl, 2-fluoro-4-chlorophenyl, 2,5-difluorophenyl,2,4,6-trifluorophenyl, or 4-bromo-2,5-difluorophenyl. In someembodiments, R is a phenyl group substituted by from 1 to 3 halo(preferably F or Cl) substituents. In some embodiments, R is a phenylgroup substituted by from 1 or 2 halo (preferably F or Cl) substituents.In some embodiments, R is 2,4-difluorophenyl, 2,4-dichlorophenyl,2-fluorophenyl or 2-chlorophenyl.

In some embodiments, the CYP51A1 inhibitor is2-(2,4-difluorophenyl)-3-(pyridin-2-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol,2-(2,4-difluorophenyl)-3-(pyridin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol,or2-(2,4-difluorophenyl)-3-(pyrimidin-4-yl)-1-(1H,1,2,4-triazol-1-yl)butan-2-ol.

In some embodiments, the CYP51A1 inhibitor is a compound represented byformula (XVIII)

wherein R is optionally substituted phenyl (e.g., substituted by from 1to 3 substituents each independently selected from halo, —CF₃ and—OCF₃);

R¹ is optionally substituted alkyl, such as optionally substituted loweralkyl (e.g., C₁-C₄ alkyl);

R₂ is H or optionally substituted alkyl, such as optionally substitutedlower alkyl (e.g., C₁-C₄ alkyl);

X is CH or N; and

Y is a halogen, such as F or Cl;

or a pharmaceutically acceptable salt, ester, or ether thereof.

Examples of R in formula (XVIII) are 2-fluorophenyl, 4-fluorophenyl,2-chlorophenyl, 4-chlorophenyl, 2-bromophenyl, 2-iodophenyl,2-trifluoromethylphenyl, 2,4-dichlorophenyl, 2,4-difluorophenyl,2-chloro-4-fluorophenyl, 2-fluoro-4-chlorophenyl, 2,5-difluorophenyl,2,4,6-trifluorophenyl, 4-bromo-2,5-difluorophenyl, and2-trifluoromethoxyphhenyl.

In some embodiments of formula (XVIII), the compound is represented byformula (XIX)

wherein R, R₁, R₂, X, and Y are as defined for formula (XVIII);

or a pharmaceutically acceptable salt, ester, or ether thereof.

In some embodiments of formula (XVIII), the compound is represented byformula (XX)

wherein R, R₁, R₂, X, and Y are as defined for formula (XVIII);

or a pharmaceutically acceptable salt, ester, or ether thereof.

In some embodiments of formula (XVIII), the compound is represented byformula (XXI)

wherein R, R₁, R₂, X, and Y are as defined for formula (XVIII);

or a pharmaceutically acceptable salt, ester, or ether thereof.

In some embodiments, the CYP51A1 inhibitor is2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol,or a pharmaceutically acceptable salt, ester, or ether thereof. In someembodiments, the CYP51A1 inhibitor is(2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol,or a pharmaceutically acceptable salt, ester, or ether thereof.

In some embodiments, the CYP51A1 inhibitor is a compound represented byformula (XXII)

wherein R₁ is an optionally substituted alkyl, cycloalkyl (e.g.cyclopentyl or cyclohexyl), aryl (e.g. phenyl) or arylalkyl (e.g.benzyl) group; and

Y₁ and Y₂ are each independently ═CH— or ═N—;

or a pharmaceutically acceptable salt, ester, or ether thereof.

In some embodiments of formula (XXII), R₁ is alkyl, cycloalkyl,optionally substituted aryl, or optionally substituted arylalkyl; and Y¹and Y² are either both ═CH— or both ═N—.

In some embodiments of formula (XXII), R₁ is phenyl or benzyl,optionally substituted with one or more of halogen, alkyl or haloalkyleach containing from 1 to 5 carbon atoms, alkoxy or haloalkoxy eachcontaining from 1 to 4 carbon atoms, nitro, cyano, hydroxy, alkylthiocontaining from 1 to 40 carbon atoms, vinyl, phenyl or phenoxy. In someembodiments, the alkyl moiety of the benzyl is unsubstituted, orsubstituted with alkyl containing from 1 to 4 carbon atoms, phenyl orchlorophenyl.

In some embodiments, the CYP51A1 inhibitor is selected from:

or a pharmaceutically acceptable salt, ester, or ether thereof.

In some embodiments, the CYP51A1 inhibitor is a compound represented byformula (XXIII)

wherein each of R₁, R₂, and R₃ is independently an aryl grouprepresented by the formula:

n is 0, 1, 2, 3, 4, or 5 (e.g., 0, 1, or 2) and each R′ is independentlyhalogen or optionally substituted alkyl (e.g., optionally substitutedlower alkyl); and

each X is independently selected from hydrogen, optionally substitutedalkyl (e.g., optionally substituted lower alkyl), or optionallysubstituted aryl (e.g., optionally substituted phenyl);

or a pharmaceutically acceptable salt, ester, or ether thereof. In someembodiments, the total number of carbon atoms in all X substituents isan integer of from 0 to 15.

In some embodiments, the CYP51A1 inhibitor is a compound selected fromI-(tris(m-tert-butylphenyl)methyl) imidazole, 1-(tris(p-tert-butylphenylmethyl) imidazole, 1-(his(2,4-difiourophenyl)methyl)-2,4,5-trimethylimidazole,1-(tris(p-chlorophenyl)methyl)-2-methyl-4,5-diphenylimidazone,1-(tris(m-tolyl)methyl)-2-n-propylimidaz-ole, and1-trityl-2-methylimidazole.

In some embodiments, the CYP51A1 inhibitor is a compound represented byformula (XXIV)

wherein each of R, R₁, and R₂ is independently hydrogen, optionallysubstituted alkyl (e.g., optionally substituted lower alkyl), oroptionally substituted and optionally fused aryl (e.g., optionallysubstituted phenyl);

each of X, X′, and X′″ is independently hydrogen, halogen, optionallysubstituted alkyl (e.g., optionally substituted lower alkyl), oroptionally substituted and optionally fused aryl (e.g., optionallysubstituted phenyl); and

each of n, n′, and n″ is independently 1, 2, 3, 4, or 5 (e.g., 1, 2, or3);

or a pharmaceutically acceptable salt, ester, or ether thereof.

In some embodiments of formula (XXIV), the compound is represented byformula (XXV)

wherein X, X′, X′″, n, n′, and n″ are as defined for formula (XXIV);

or a pharmaceutically acceptable salt, ester, or ether thereof.

In some embodiments of formula (XXIV), the compound is represented byformula (XXVI)

wherein X, X′, X′″, n, n′, and n″ are as defined for formula (XXIV);

or a pharmaceutically acceptable salt, ester, or ether thereof.

In some embodiments, the CYP51A1 inhibitor is1-(3,4-Dimethylphenyl-phenyl-2-pyridyl)-methyl-imidazole,1-(2,4-dimethylphenyl-phenyl-2-pyridyl)-methyl-imidazole,1-(2,6-dimethylphenyl-phenyl-2-pyridyl)-methyl-imidazole,1-(2,4-dimethylphenyl-phenyl-4-pyridyl)-methyl-imidazole,1-(3,4-dimethylphenyl-phenyl-4-pyridyl)-methyl-imidazole,1-(2,5-dimethylphenyl-phenyl-4-pyridyl)-methyl-imidazole,1-(2,3-dimethylphenyl-phenyl-2-pyridyl)-methyl-imidazole,1-(2,3-dimethylphenyl-phenyl-2-pyridyl)-methyl-imidazole,1-(2,3-dimethylphenyl-phenyl-2-pyridyl)-methyl-imidazole,1-(2,3-dimethylphenyl-phenyl-4-pyridyl)-methyl-imidazole,1-(3,4-dimethylphenyl-phenyl-4-pyridyl)-methyl-imidazole, or apharmaceutically acceptable salt thereof, such as the1,5-naphthalene-disulphonate salt thereof or the hydrochloride saltthereof.

In some embodiments, the CYP51A1 inhibitor is a compound represented byformula (XXVII)

wherein A and B are independently selected from optionally substitutedalkyl (e.g., optionally substituted lower alkyl, such as alkyl of 1 to 4carbon atoms), optionally substituted naphthyl, optionally substitutedbiphenyl, and optionally substituted phenyl, and Z is CH or N;

or a pharmaceutically acceptable salt, ester, or ether thereof.

In some embodiments of formula (XXVII), A and/or B is an optionallysubstituted phenyl group, such as a phenyl group substituted by one ormore of halogen, nitro, alkyl (e.g., of from 1 to 4 carbon atoms),alkoxy (e.g., of from 1 to 4 carbon atoms), haloalkyl (e.g., of from 1to 4 carbon atoms), phenoxy, or phenylsulyfonyl.

In some embodiments, the CYP51A1 inhibitor is a compound represented byformula (XXVIII)

wherein R is optionally substituted aryl, such as phenyl, pyridyl,tetrahydropyranyl, norbornyl, C₃-C₁₂ cycloalkyl or C₅-C₈ cycloalkenyl,each of which may be unsubstituted or monosubstituted to trisubstitutedby halogen, nitro, phenoxy, alkyl, amino, alkoxy (e.g., of from 1 to 4carbon atoms), haloalkoxy (e.g., of from 1 to 4 carbon atoms), orhaloalkyl (e.g., of from 1 to 4 carbon atoms);

each X is independently fluorine, chlorine, bromine, or iodine; and

each n is independently 1, 2, 3, 4, or 5 (e.g., 1, 2, or 3);

or a pharmaceutically acceptable salt, ester, or ether thereof.

In some embodiments of formula (XXVIII), the compound is represented byformula (XXIX)

wherein R and X are as defined for formula (XXVIII);

or a pharmaceutically acceptable salt, ester, or ether thereof.

In some embodiments of formula (XXVIII), the compound is represented byformula (XXX)

wherein R is as defined for formula (XXVIII);

or a pharmaceutically acceptable salt, ester, or ether thereof.

In some embodiments, the CYP51A1 inhibitor is a compound represented byformula (XXXI)

wherein each of rings A and B are independently optionally substitutedand optionally fused aryl, heteroaryl, cycloalkyl, or heterocycloalkyl;

each X is independently halogen or optionally substituted alkyl (e.g.,optionally substituted lower alkyl); and

n is 1, 2, 3, 4, or 5 (e.g., 1, 2, or 3);

or a pharmaceutically acceptable salt, ester, or ether thereof.

In some embodiments of formula (XXXI), the compound is represented byformula (XXXII)

wherein each X is independently halogen or optionally substituted alkyl(e.g., optionally substituted lower alkyl); and

each n is independently 1, 2, 3, 4, or 5 (e.g., 1, 2, or 3);

or a pharmaceutically acceptable salt, ester, or ether thereof.

In some embodiments of formula (XXXII), the compound is represented byformula (XXXIII)

wherein each X and n are as defined for formula (XXXII);

or a pharmaceutically acceptable salt, ester, or ether thereof.

In some embodiments, the CYP51A1 inhibitor is represented by theformula:

In some embodiments, the CYP51A1 inhibitor is a compound represented byformula (XXXIV)

wherein each X is independently halogen or optionally substituted alkyl(e.g., optionally substituted lower alkyl); and

each n is independently 1, 2, 3, 4, or 5 (e.g., 1, 2, or 3);

or a pharmaceutically acceptable salt, ester, or ether thereof.

In some embodiments of formula (XXXIV), the compound is represented byformula (XXXV)

wherein each X and n are as defined for formula (XXXIV);

or a pharmaceutically acceptable salt, ester, or ether thereof.

In some embodiments, the CYP51A1 inhibitor is represented by theformula:

In some embodiments, the CYP51A1 inhibitor is a compound represented byformula (XXXVI)

wherein Q is selected from the group consisting of CH and N;

Ar is an optionally substituted, optionally fused aryl group, such as anoptionally fused, optionally substituted phenyl group, for example, aphenyl group having from 1 to 3 substituents, such as from 1 to 3substituents independently selected from the group consisting of halo,lower alkyl and lower alkyloxy;

A is selected from the group consisting of:

-   -   (a) an isothiocyanato group —N═C═S;    -   (b) an amino group of the formula

-   -   wherein R₁ and R₂ are each independently selected from the group        consisting of hydrogen and lower alkyl;    -   (c) a group of the formula

-   -   wherein X is selected from the group consisting of O and S, Y is        selected from the group consisting of O and NH, m is the integer        0 or 1, and R₃ is selected from the group consisting of        hydrogen, lower alkyl, mono- and dihalo-(lower alkyl), phenyl        and substituted phenyl, said substituted phenyl having from 1 to        2 substituents independently selected from the group consisting        of halo, lower alkyl and lower alkyloxy, optionally provided        that:        -   i) when said X is S, then said Y is NH and said m is 1; and        -   ii) when said Y is O and said m is 1, then said R₃ is other            than hydrogen; and    -   (d) a group of the formula

-   -   wherein Z is selected from the group consisting of a direct        bond, CH₂, O and N—R₄, wherein R₄ is selected from the group        consisting of hydrogen, lower alkyl, hydroxy-(lower alkyl),        (lower alkyloxy)-lower alkyl, lower alkanoyl, lower        alkylsulfonyl, phenylmethylsulfonyl, lower alkyloxycarbonyl,        lower alkyloxycarbonylmethyl, phenoxycarbonyl, aminocarbonyl,        mono- and di(lower alkyl)aminocarbonyl, aminocarbonylmethyl,        (lower alkyl)aminocarbonylmethyl, (lower        alkyl)aminothioxomethyl, (lower alkylthio)thioxomethyl, phenyl,        phenylmethyl, benzoyl and substituted benzoyl, said substituted        benzoyl being benzoyl having from 1 to 2 substituents        independently selected from the group consisting of halo, lower        alkyl and lower alkyloxy; and R is selected from the group        consisting of hydrogen and nitro, optionally provided that when        said R is nitro, then said A is amino;

or a pharmaceutically acceptable salt, ester, or ether thereof.

In some embodiments, the CYP51A1 inhibitor is a compound represented byformula (XXXVII)

wherein Q is selected from the group consisting of N and CH;

Ar is selected from the group consisting of phenyl, thienyl, halothienyland substituted phenyl, the substituted phenyl having from 1 to 3substituents each independently selected from the group consisting ofhalo, lower alkyl, lower alkyloxy and trifluoromethyl; and

the group Y is selected from the group consisting of:

-   -   a group of the formula —SO₂R₁, wherein R₁ is selected from the        group consisting of trifluoromethyl and aryl;    -   a group of formula -alk-R₂, wherein alk is selected from the        group consisting of lower alkylene and lower alkenylene and R₂        is selected from the group consisting of cyano, amino, mono- and        di(lower alkyl)amino, arylamino, mono- and di(aryllower        alkyl)amino, 1-pyrrolidinyl, 1-morpholinyl, 1-piperidinyl,        aryloxy and aryl, provided that alk is other than methylene when        R₂ is phenyl;    -   a group of formula

-   -   wherein n is an integer of from 0 to 6 inclusive, X is O or S        and R₃ is selected from the group consisting of hydrogen, mono-,        di- and trihalo lower alkyl, amino, mono- and di(lower        alkyl)amino, arylamino, mono- and di(aryllower alkyl)amino,        amino lower alkyl, mono- and di(lower alkyl)amino lower alkyl,        (1-pyrrolidinyl)lower alkyl, (1-morpholinyl)lower alkyl,        (1-piperidinyl)lower alkyl, aryl, aryllower alkyl, aryllower        alkenyl and lower alkyloxycarbonyl lower alkyloxy, optionally        provided that:        -   (i) said n is other than 0 or 1 when said R₃ is amino or            lower alkylamino; and        -   (ii) said n is other than 0 when said R₃ is di(lower            alkyl)amino or aryl; and    -   a group of formula

-   -   wherein m is an integer of from 1 to 6 inclusive, A is O or NH,        X is O or S and R₄ is selected from the group consisting of        hydrogen, lower alkyl, lower alkyloxy, aryl, aryloxy, aryllower        alkyl, amino, mono- and di(lower alkyl)amino, arylamino, mono-        and di(aryllower alkyl)amino, 1-pyrrolidinyl, 1-morpholinyl and        1-piperidinyl;        wherein said aryl, as used in the foregoing definitions, is        selected from the group consisting of phenyl, substituted        phenyl, thienyl, halothienyl, lower alkylthienyl and pyridinyl,        said substituted phenyl optionally being a phenyl ring having        from 1 to 3 substituents each independently selected from the        group consisting of lower alkyl, lower alkyloxy, halo, amino,        mono- and di(lower alkyl)amino, lower alkylcarbonylamino, nitro        and trifluoromethyl;

or a pharmaceutically acceptable salt, ester, or ether thereof.

In some embodiments, the CYP51A1 inhibitor is a compound represented byformula (XXXVIII)

wherein X is oxygen or sulfur, R₁ is optionally substituted alkyl,alkenyl, alkynyl, cycloalkyl, phenyl, phenylalkyl, phenylalkenyl,phenoxyalkyl or phenylthioalkyl and R₂ is optionally substituted phenyl,phenylalkyl, phenylalkenyl, phenoxyalkyl or phenylthioalkyl, providedthat when R₁ is methyl or phenyl R₂ is substituted phenyl or optionallysubstituted phenylalkyl, phenylalkenyl, phenoxyalkyl or phenylthioalkyl;

or a pharmaceutically acceptable salt, ester, or ether thereof.

In some embodiments of formula (XXXVIII), X is selected from the groupconsisting of oxygen and sulfur, R₁ is selected from the groupconsisting of alkyl of 1 to 10 carbon atoms, alkenyl of 3 or 4 carbonatoms, alkynyl of 3 to 5 carbon atoms, cycloalkyl of 3 to 10 carbonatoms, optionally substituted phenyl, phenylalkyl, of the formulaPh(CH₂)_(n) where n is 1 to 5, phenylalkenyl of 9 to 11 carbon atoms,phenoxyalkyl of the formula PhO(CH₂)_(n) where n is 2 to 5 andphenylthioalkyl of the formula PhS(CH₂)_(n) where n is 2 to 5, whereinthe substituted phenyl nucleus has at least one substituent selectedfrom the group consisting of halo, alkoxy of 1 or 2 carbon atoms, alkylof 1 to 4 carbon atoms, trihalomethyl, cyano, methylthio, nitro andmethylsulphonyl, and R₂ is selected from the group consisting ofoptionally substituted phenylalkyl, of the formula Ph(CH₂)_(n) where nis 1 to 5, phenylalkenyl of 9 to 11 carbon atoms, phenoxyalkyl of theformula PhO(CH₂)_(n) where n is 2 to 5 and phenylthioalkyl of theformula PhS(CH₂)_(n) where n is 2 to 5, wherein the substituted phenylnucleus has at least one substituent selected from the group consistingof halo, alkoxy of 1 or 2 carbon atoms, alkyl of 1 to 4 carbon atoms,trihalomethyl, cyano, methylthio, nitro and methylsulphonyl.

In some embodiments, the CYP51A1 inhibitor is prochloraz, represented byformula (7)

In some embodiments, the CYP51A1 inhibitor is a compound represented byformula (XXXIX)

wherein Z is an alkylene selected from the group consisting of —CH₂CH₂—,—CH₂—CH₂CH₂—, —CH(CH₃)CH(CH₃)—, and —CH₂CH(alkyl)-, wherein the alkylhas from 1 to about 10 carbon atoms; and

Ar is an optionally fused, optionally substituted aryl group, such as anoptionally fused, optionally substituted phenyl, thienyl, naphthyl, orfluorenyl, for example, phenyl, thienyl, halothienyl, naphthyl andfluorenyl, each optionally containing one or more (e.g., from 1 to 3)substituents, such as substituents selected independently from the groupconsisting of halo, lower alkyl, lower alkyloxy, cyano, and nitro;

or a pharmaceutically acceptable salt, ester, or ether thereof.

In some embodiments, the CYP51A1 inhibitor is propiconazole, representedby formula (8)

In some embodiments, the CYP51A1 inhibitor is a compound represented byformula (XL)

wherein R₁ and R₂ are each independently selected from optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted cycloalkyl, optionally substituted aralkyl, optionallysubstituted aralkenyl, optionally substituted aroxyalkyl, optionallysubstituted aryl, and optionally substituted heteroaryl; and

X is —SH, —SR₃, —SO—R₃, —SO₂—R₃, or —SO₃H, wherein R₃ is alkyl which isoptionally substituted by one or more halogen moieties (e.g., fluorineand/or chlorine), alkenyl which is optionally substituted by one or morehalogen moieties (e.g., fluorine and/or chlorine), optionallysubstituted aralkyl or optionally substituted aryl;

or a pharmaceutically acceptable salt, ester, or ether thereof.

In some embodiments, the CYP51A1 inhibitor is prothioconazole,represented by formula (8)

In some embodiments, the CYP51A1 inhibitor is prothioconazole-desthio,represented by formula (9)

In some embodiments, the CYP51A1 inhibitor is a compound represented byformula (XLI)

wherein R₁ is —CH═CH—X, —C≡C—X, or —CH₂—CH₂—X, wherein X is hydrogen,alkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl or optionally substitutedaryl, aralkyl, aryloxy alkyl, or heterocycle;

R₂ is alkyl, cycloalkyl (e.g. cyclopropyl, cyclopentyl, or cyclohexyl)or optionally substituted aryl;

Z is Cl, CN, or OR₃, wherein R₃ is hydrogen, acetyl, alkyl, alkenyl oraralkyl; and

Y is ═N— or ═CH—,

or a pharmaceutically acceptable salt, ester, or ether thereof.

In some embodiments, the CYP51A1 inhibitor is tebuconazole, representedby formula (10)

In some embodiments, the CYP51A1 inhibitor is a compound represented byformula (XLII)

wherein X₁ is hydrogen or an alkyl group,

X₂ is hydrogen or an alkyl group,

R₁ is an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl or optionallysubstituted aryl or aralkyl group,

R₂ is hydrogen or an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenylor optionally substituted aryl or aralkyl group,

R₃ is hydrogen or an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenylor optionally substituted aryl or aralkyl group, and

Y is a keto group or a functional keto derivative.

or a pharmaceutically acceptable salt, ester, or ether thereof.

In some embodiments, the CYP51A1 inhibitor is triadimenol, representedby formula (11)

In some embodiments, the CYP51A1 inhibitor is a compound represented byformula (XLIII)

wherein n is 2 or 3;

p is 0, 1 or 2;

q is 0, 1 or 2;

X is oxygen or S(O)_(t) wherein t is 0, 1, or 2;

each R₁ is independently halo, lower alkyl, lower alkoxy, ortrifluoromethyl;

each R₂ is independently halo or lower alkyl;

R₃ is nitro or —N(R₅)R₆ where

R₅ is hydrogen or lower alkyl;

R₆ is hydrogen, lower alkyl, lower alkylsulfonyl or —C(Y)R₇ where Y isoxygen or sulfur and R₇ is hydrogen, lower alkyl, lower alkoxy or—N(R₈)R₉ where R₈ is hydrogen or lower alkyl and R₉ is hydrogen, loweralkyl or lower alkoxycarbonyl; or

R₅ and R₆ together with N is pyrrolidino, piperidino, morpholino,thiomorpholino or piperazino, wherein the piperazino is optionallysubstituted at the 4-position by —C(O)R₁₀ where R₁₀ is hydrogen, loweralkyl, lower alkoxy or amino; and

R₄ is hydrogen or optionally substituted lower alkyl;

or a pharmaceutically acceptable salt, ester, or ether thereof.

In some embodiments of formula (XLIII), the compound is represented byformula (XLIV)

wherein R₁, R₂, R₃, R₄, X, n, p, and q are as defined for formula(XLIII);

or a pharmaceutically acceptable salt, ester, or ether thereof.

In some embodiments of formula (XLIII), the compound is represented byformula (XLV)

wherein R₁, R₂, R₃, R₄, X, n, p, and q are as defined for formula(XLIII);

or a pharmaceutically acceptable salt, ester, or ether thereof.

In some embodiments of formula (XLIII), the compound is represented byformula (XLVI)

wherein R₁, R₂, R₃, R₄, X, n, p, and q are as defined for formula(XLIII);

or a pharmaceutically acceptable salt, ester, or ether thereof.

In some embodiments of formula (XLIII), the compound is represented byformula (XLVII)

wherein R₁, R₂, R₃, R₄, X, n, p, and q are as defined for formula(XLIII);

or a pharmaceutically acceptable salt, ester, or ether thereof.

In some embodiments of formula (XLIII), the compound is represented byformula (XLVIII)

wherein R₁, R₂, R₃, R₄, X, n, p, and q are as defined for formula(XLIII);

or a pharmaceutically acceptable salt, ester, or ether thereof.

In some embodiments, the CYP51A1 inhibitor is azalanstat, represented byformula (12)

In some embodiments, the CYP51A1 inhibitor is LEK-935, CP-320626,itraconazole, posaconazole, cyproconazole, voriconazole, fluconazole,clotrimazol, fenticonazole, epoxiconazole, ketoconazole, ravuconazole,isavuconazole, holothurin A, theasaponin, capsicosine,betulafolientriol, prochloraz, propiconazole, prothioconazole,prothioconazole-desthio, tebuconazole, triadimenol, azalanstat, or avariant thereof.

In some embodiments, the CYP51A1 inhibitor is an antibody orantigen-binding fragment thereof, such as one that specifically binds toCYP51A1 and/or inhibits CYP51A1 catalytic activity. In some embodiments,the antibody or antigen-binding fragment thereof is a monoclonalantibody or antigen-binding fragment thereof, a polyclonal antibody orantigen-binding fragment thereof, a humanized antibody orantigen-binding fragment thereof, a bispecific antibody orantigen-binding fragment thereof, a dual-variable immunoglobulin domain,a single-chain Fv molecule (scFv), a diabody, a triabody, a nanobody, anantibody-like protein scaffold, a Fv fragment, a Fab fragment, a F(ab′)₂molecule, and a tandem di-scFv. In some embodiments, the antibody has anisotype selected from IgG, IgA, IgM, IgD, and IgE.

In some embodiments, the CYP51A1 inhibitor is an interfering RNAmolecule, such as a short interfering RNA (siRNA), micro RNA (miRNA), orshort hairpin RNA (shRNA). The interfering RNA may suppress expressionof a CYP51A1 mRNA transcript, for example, by way of (i) annealing to aCYP51A1 mRNA or pre-mRNA transcript, thereby forming a nucleic acidduplex; and (ii) promoting nuclease-mediated degradation of the CYP51A1mRNA or pre-mRNA transcript and/or (iii) slowing, inhibiting, orpreventing the translation of a CP51A1 mRNA transcript, such as bysterically precluding the formation of a functional ribosome-RNAtranscript complex or otherwise attenuating formation of a functionalprotein product from the target RNA transcript.

In some embodiments, the interfering RNA molecule, such as the siRNA,miRNA, or shRNA, contains an antisense portion that anneals to a segmentof a CYP51A1 RNA transcript (e.g., mRNA or pre-mRNA transcript), such asa portion that anneals to a segment of a CYP51A1 RNA transcript having anucleic acid sequence that is at least 85% identical to the nucleic acidsequence of SEQ ID NO: 2 (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%,93%, 94%, 95%<96%, 97%, 98%, 99%, 99.9%, or 100% identical to thenucleic acid sequence of SEQ ID NO: 2).

In some embodiments, the interfering RNA molecule, such as the siRNA,miRNA, or shRNA, contains a sense portion having at least 85% sequenceidentity to the nucleic acid sequence of a segment of SEQ ID NO: 2(e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%<96%, 97%,98%, 99%, 99.9%, or 100% identical to the nucleic acid sequence of asegment of SEQ ID NO: 2).

In some embodiments, the neurological disorder is amyotrophic lateralsclerosis, and following administration of the CYP51A1 inhibitor to thepatient, the patient exhibits one or more, or all, of the followingresponses:

(i) an improvement in condition as assessed using the amyotrophiclateral sclerosis functional rating scale (ALSFRS) or the revised ALSFRS(ALSFRS-R), such as an improvement in the patient's ALSFRS or ALSFRS-Rscore within one or more days, weeks, or months following administrationof the CYP51A1 inhibitor (e.g., an improvement in the patient's ALSFRSor ALSFRS-R score within from about 1 day to about 48 weeks (e.g.,within from about 2 days to about 36 weeks, from about 4 weeks to about24 weeks, from about 8 weeks to about 20 weeks, or from about 12 weeksto about 16 weeks), or more, following the initial administration of theCYP51A1 inhibitor to the patient, such as within 1 day, 2 days, 3 days,4 days, 5 days, 6 days, 7 days, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48weeks, or more, following the initial administration of the CYP51A1inhibitor to the patient);

(ii) an increase in slow vital capacity, such as an increase in thepatient's slow vital capacity within one or more days, weeks, or monthsfollowing administration of the CYP51A1 inhibitor (e.g., an increase inthe patient's slow vital capacity within from about 1 day to about 48weeks (e.g., within from about 2 days to about 36 weeks, from about 4weeks to about 24 weeks, from about 8 weeks to about 20 weeks, or fromabout 12 weeks to about 16 weeks), or more, following the initialadministration of the CYP51A1 inhibitor to the patient, such as within 1day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 2 weeks, 3 weeks, 4weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks,12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47weeks, 48 weeks, or more, following the initial administration of theCYP51A1 inhibitor to the patient);

(iii) a reduction in decremental responses exhibited by the patient uponrepetitive nerve stimulation, such as a reduction that is observedwithin one or more days, weeks, or months following administration ofthe CYP51A1 inhibitor (e.g., a reduction that is observed within fromabout 1 day to about 48 weeks (e.g., within from about 2 days to about36 weeks, from about 4 weeks to about 24 weeks, from about 8 weeks toabout 20 weeks, or from about 12 weeks to about 16 weeks), or more,following the initial administration of the CYP51A1 inhibitor to thepatient, such as within 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7days, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44weeks, 45 weeks, 46 weeks, 47 weeks, 48 weeks, or more, following theinitial administration of the CYP51A1 inhibitor to the patient);

(iv) an improvement in muscle strength, as assessed, for example, by wayof the Medical Research Council muscle testing scale (as described,e.g., in Jagtap et al., Ann. Indian. Acad. Neurol. 17:336-339 (2014),the disclosure of which is incorporated herein by reference as itpertains to measuring patient response to neurological diseasetreatment), such as an improvement that is observed within one or moredays, weeks, or months following administration of the CYP51A1 inhibitor(e.g., an improvement that is observed within from about 1 day to about48 weeks (e.g., within from about 2 days to about 36 weeks, from about 4weeks to about 24 weeks, from about 8 weeks to about 20 weeks, or fromabout 12 weeks to about 16 weeks), or more, following the initialadministration of the CYP51A1 inhibitor to the patient, such as within 1day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 2 weeks, 3 weeks, 4weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks,12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47weeks, 48 weeks, or more, following the initial administration of theCYP51A1 inhibitor to the patient);

(v) an improvement in quality of life, as assessed, for example, usingthe amyotrophic lateral sclerosis-specific quality of life (ALS-specificQOL) questionnaire, such as an improvement in the patient's quality oflife that is observed within one or more days, weeks, or monthsfollowing administration of the CYP51A1 inhibitor (e.g., an improvementin the subject's quality of life that is observed within from about 1day to about 48 weeks (e.g., within from about 2 days to about 36 weeks,from about 4 weeks to about 24 weeks, from about 8 weeks to about 20weeks, or from about 12 weeks to about 16 weeks), or more, following theinitial administration of the CYP51A1 inhibitor to the patient, such aswithin 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 2 weeks, 3weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks,11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46weeks, 47 weeks, 48 weeks, or more, following the initial administrationof the CYP51A1 inhibitor to the patient);

(vi) a decrease in the frequency and/or severity of muscle cramps, suchas a decrease in cramp frequency and/or severity within one or moredays, weeks, or months following administration of the CYP51A1 inhibitor(e.g., a decrease in cramp frequency and/or severity within from about 1day to about 48 weeks (e.g., within from about 2 days to about 36 weeks,from about 4 weeks to about 24 weeks, from about 8 weeks to about 20weeks, or from about 12 weeks to about 16 weeks), or more, following theinitial administration of the CYP51A1 inhibitor to the patient, such aswithin 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 2 weeks, 3weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks,11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46weeks, 47 weeks, 48 weeks, or more, following the initial administrationof the CYP51A1 inhibitor to the patient); and/or

(vii) a decrease in TDP-43 aggregation, such as a decrease in TDP-43aggregation within one or more days, weeks, or months followingadministration of the CYP51A1 inhibitor (e.g., a decrease in TDP-43aggregation within from about 1 day to about 48 weeks (e.g., within fromabout 2 days to about 36 weeks, from about 4 weeks to about 24 weeks,from about 8 weeks to about 20 weeks, or from about 12 weeks to about 16weeks), or more, following the initial administration of the CYP51A1inhibitor to the patient, such as within 1 day, 2 days, 3 days, 4 days,5 days, 6 days, 7 days, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 weeks, ormore, following the initial administration of the CYP51A1 inhibitor tothe patient.

In another aspect, the invention features a kit containing a CYP51A1inhibitor. The kit may further contain a package insert, such as onethat instructs a user of the kit to perform the method of any of theabove aspects or embodiments of the invention. The CYP51A1 inhibitor inthe kit may be a small molecule, antibody, antigen-binding fragmentthereof, or interfering RNA molecule, such as a small molecule,antibody, antigen-binding fragment thereof, or interfering RNA moleculedescribed above and herein.

Definitions

As used herein, the term “about” refers to a value that is within 10%above or below the value being described. For instance, a value of“about 5 mg” refers to a quantity that is from 4.5 mg to 5.5 mg.

As used herein, the term “affinity” refers to the strength of a bindinginteraction between two molecules, such as a ligand and a receptor. Theterm “K_(i)”, as used herein, is intended to refer to the inhibitionconstant of an antagonist for a particular molecule of interest, and isexpressed as a molar concentration (M). K_(i) values forantagonist-target interactions can be determined, e.g., using methodsestablished in the art. The term “K_(d)”, as used herein, is intended torefer to the dissociation constant, which can be obtained, e.g., fromthe ratio of the rate constant for the dissociation of the two molecules(k_(d)) to the rate constant for the association of the two molecules(k_(a)) and is expressed as a molar concentration (M). K_(d) values forreceptor-ligand interactions can be determined, e.g., using methodsestablished in the art. Methods that can be used to determine the K_(d)of a receptor-ligand interaction include surface plasmon resonance,e.g., through the use of a biosensor system such as a BIACORE® system.

As used herein, the terms “benefit” and “response” are usedinterchangeably in the context of a subject, such as a human subjectundergoing therapy for the treatment of a neurological disorder, forexample, amyotrophic lateral sclerosis, frontotemporal degeneration(also referred to as frontotemporal lobar degeneration andfrontotemporal dementia), Alzheimer's disease, Parkinson's disease,dementia with Lewy Bodies, corticobasal degeneration, progressivesupranuclear palsy, dementia parkinsonism ALS complex of Guam,Huntington's disease, Inclusion body myopathy with early-onset Pagetdisease and frontotemporal dementia (IBMPFD), sporadic inclusion bodymyositis, myofibrillar myopathy, dementia pugilistica, chronic traumaticencephalopathy, Alexander disease, and hereditary inclusion bodymyopathy. The terms “benefit” and “response” refer to any clinicalimprovement in the subject's condition. Exemplary benefits in thecontext of a subject undergoing treatment for a neurological disorderusing the compositions and methods described herein (e.g., in thecontext of a human subject undergoing treatment for a neurologicaldisorder described herein, such as amyotrophic lateral sclerosis, with acytochrome P450 isoform 51A1 (CYP51A1) inhibitor described herein, suchas an inhibitory small molecule, antibody, antigen-binding fragmentthereof, or interfering RNA molecule) include the slowing and halting ofdisease progression, as well as suppression of one or more symptomsassociated with the disease. Particularly, in the context of a patient(e.g., a human patient) undergoing treatment for amyotrophic lateralsclerosis with a CYP51A1 inhibitor described herein, examples ofclinical “benefits” and “responses” are (i) an improvement in thesubject's condition as assessed using the amyotrophic lateral sclerosisfunctional rating scale (ALSFRS) or the revised ALSFRS (ALSFRS-R)following administration of the CYP51A1 inhibitor, such as animprovement in the subject's ALSFRS or ALSFRS-R score within one or moredays, weeks, or months following administration of the CYP51A1 inhibitor(e.g., an improvement in the subject's ALSFRS or ALSFRS-R score withinfrom about 1 day to about 48 weeks (e.g., within from about 2 days toabout 36 weeks, from about 4 weeks to about 24 weeks, from about 8 weeksto about 20 weeks, or from about 12 weeks to about 16 weeks), or more,following the initial administration of the CYP51A1 inhibitor to thesubject, such as within 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7days, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44weeks, 45 weeks, 46 weeks, 47 weeks, 48 weeks, or more, following theinitial administration of the CYP51A1 inhibitor to the subject); (ii) anincrease in the subject's slow vital capacity following administrationof the CYP51A1 inhibitor, such as an increase in the subject's slowvital capacity within one or more days, weeks, or months followingadministration of the CYP51A1 inhibitor (e.g., an increase in thesubject's slow vital capacity within from about 1 day to about 48 weeks(e.g., within from about 2 days to about 36 weeks, from about 4 weeks toabout 24 weeks, from about 8 weeks to about 20 weeks, or from about 12weeks to about 16 weeks), or more, following the initial administrationof the CYP51A1 inhibitor to the subject, such as within 1 day, 2 days, 3days, 4 days, 5 days, 6 days, 7 days, 2 weeks, 3 weeks, 4 weeks, 5weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks,13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48weeks, or more, following the initial administration of the CYP51A1inhibitor to the subject); (iii) a reduction in decremental responsesexhibited by the subject upon repetitive nerve stimulation, such as areduction that is observed within one or more days, weeks, or monthsfollowing administration of the CYP51A1 inhibitor (e.g., a reductionthat is observed within from about 1 day to about 48 weeks (e.g., withinfrom about 2 days to about 36 weeks, from about 4 weeks to about 24weeks, from about 8 weeks to about 20 weeks, or from about 12 weeks toabout 16 weeks), or more, following the initial administration of theCYP51A1 inhibitor to the subject, such as within 1 day, 2 days, 3 days,4 days, 5 days, 6 days, 7 days, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48weeks, or more, following the initial administration of the CYP51A1inhibitor to the subject); (iv) an improvement in the subject's musclestrength, as assessed, for example, by way of the Medical ResearchCouncil muscle testing scale (as described, e.g., in Jagtap et al., Ann.Indian. Acad. Neurol. 17:336-339 (2014), the disclosure of which isincorporated herein by reference as it pertains to measuring patientresponse to neurological disease treatment), such as an improvement thatis observed within one or more days, weeks, or months followingadministration of the CYP51A1 inhibitor (e.g., an improvement that isobserved within from about 1 day to about 48 weeks (e.g., within fromabout 2 days to about 36 weeks, from about 4 weeks to about 24 weeks,from about 8 weeks to about 20 weeks, or from about 12 weeks to about 16weeks), or more, following the initial administration of the CYP51A1inhibitor to the subject, such as within 1 day, 2 days, 3 days, 4 days,5 days, 6 days, 7 days, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 weeks, ormore, following the initial administration of the CYP51A1 inhibitor tothe subject); (v) an improvement in the subject's quality of life, asassessed, for example, using the amyotrophic lateral sclerosis-specificquality of life (ALS-specific QOL) questionnaire, such as an improvementin the subject's quality of life that is observed within one or moredays, weeks, or months following administration of the CYP51A1 inhibitor(e.g., an improvement in the subject's quality of life that is observedwithin from about 1 day to about 48 weeks (e.g., within from about 2days to about 36 weeks, from about 4 weeks to about 24 weeks, from about8 weeks to about 20 weeks, or from about 12 weeks to about 16 weeks), ormore, following the initial administration of the CYP51A1 inhibitor tothe subject, such as within 1 day, 2 days, 3 days, 4 days, 5 days, 6days, 7 days, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 weeks, or more,following the initial administration of the CYP51A1 inhibitor to thesubject); and (vi) a decrease in the frequency and/or severity of musclecramps exhibited by the subject, such as a decrease in cramp frequencyand/or severity within one or more days, weeks, or months followingadministration of the CYP51A1 inhibitor (e.g., a decrease in crampfrequency and/or severity within from about 1 day to about 48 weeks(e.g., within from about 2 days to about 36 weeks, from about 4 weeks toabout 24 weeks, from about 8 weeks to about 20 weeks, or from about 12weeks to about 16 weeks), or more, following the initial administrationof the CYP51A1 inhibitor to the subject, such as within 1 day, 2 days, 3days, 4 days, 5 days, 6 days, 7 days, 2 weeks, 3 weeks, 4 weeks, 5weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks,13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48weeks, or more, following the initial administration of the CYP51A1inhibitor to the subject).

As used herein, the terms “conservative mutation,” “conservativesubstitution,” or “conservative amino acid substitution” refer to asubstitution of one or more amino acids for one or more different aminoacids that exhibit similar physicochemical properties, such as polarity,electrostatic charge, and steric volume. These properties are summarizedfor each of the twenty naturally-occurring amino acids in Table 1 below.

TABLE 1 Representative physicochemical properties of naturally-occurringamino acids Electrostatic 3 1 Side- character at Letter Letter chainphysiological Steric Amino Acid Code Code Polarity pH (7.4) Volume^(†)Alanine Ala A nonpolar neutral small Arginine Arg R polar cationic largeAsparagine Asn N polar neutral intermediate Aspartic acid Asp D polaranionic intermediate Cysteine Cys C nonpolar neutral intermediateGlutamic acid Glu E polar anionic intermediate Glutamine Gln Q polarneutral intermediate Glycine Gly G nonpolar neutral small Histidine HisH polar Both neutral large and cationic forms in equilibrium at pH 7.4Isoleucine Ile I nonpolar neutral large Leucine Leu L nonpolar neutrallarge Lysine Lys K polar cationic large Methionine Met M nonpolarneutral large Phenylalanine Phe F nonpolar neutral large Proline Pro Pnonpolar neutral intermediate Serine Ser S polar neutral small ThreonineThr T polar neutral intermediate Tryptophan Trp W nonpolar neutral bulkyTyrosine Tyr Y polar neutral large Valine Val V nonpolar neutralintermediate ^(†)based on volume in A³: 50-100 is small, 100-150 isintermediate, 150-200 is large, and >200 is bulky

From this table it is appreciated that the conservative amino acidfamilies include, e.g., (i) G, A, V, L, I, P, and M; (ii) D and E; (iii)C, S and T; (iv) H, K and R; (v) N and Q; and (vi) F, Y and W. Aconservative mutation or substitution is therefore one that substitutesone amino acid for a member of the same amino acid family (e.g., asubstitution of Ser for Thr or Lys for Arg).

As used herein, the terms “cytochrome P450 isoform 51A1,” “CYP51A1,” and“lanosterol 14-alpha demethylase” are used interchangeably and refer tothe enzyme that catalyzes the conversion of lanosterol to4,4-dimethylcholesta-8(9),14,24-trien-3β-ol, for example, in humansubjects. The terms “cytochrome P450 isoform 51A1,” “CYP51A1,” and“lanosterol 14-alpha demethylase” refer not only to wild-type forms ofCYP51A1, but also to variants of wild-type CYP51A1 proteins and nucleicacids encoding the same. The amino acid sequence and corresponding mRNAsequence of a wild-type form of human CYP51A1 are provided herein as SEQID NOs: 1 and 2, which correspond to GenBank Accession No. AAC50951.1and NCBI Reference Sequence NO. NM_000786.3, respectively. Thesesequences are shown in Table 2, below.

TABLE 2Amino acid and mRNA nucleic acid sequences of wild-type human CYP5A1SEQ ID NO. Sequence 1MLLLGLLQAGGSVLGQAMEKVTGGNLLSMLLIACAFTLSLVYLIRLAAGHLVQLPAGVKSPPYIFSPIPFLGHAIAFGKSPIEFLENAYEKYGPVFSFTMVGKTFTYLLGSDAAALLFNSKNEDLNAEDVYSRLTTPVFGKGVAYDVPNPVFLEQKKMLKSGLNIANFKQHVSIIEKETKEYFESWGESGEKNVFEALSELIILTASHCLHGKEIRSQLNEKVAQLYADLDGGFSHAAWLLPGWLPLPSFRRRDRAHREIKDIFYKAIQKRRQSQEKIDDILQTLLDATYKDGRPLTDDEVAGMLIGLLLAGQHTSSTTSAWMGFFLARDKTLQKKCYLEQKTVCGENLPPLTYDQLKDLNLLDRCIKETLRLRPPIMIMMRMARTPQTVAGYTIPPGHQVCVSPTVNQRLKDSWVERLDFNPDRYLQDNPASGEKFAYVPFGAGRHRCIGENFAYVQIKTIWSTMLRLYEFDLIDGYFPTVNYTTMIHTPENPVIRYKRRSK 2GUGACGCACGGGGUGGCGCGCGUGGGACCCGAGGGGUGGGGCUGGGUUUAGUAGGAGACCUGGGGCAAGGCCCCCUGUGGACGACCAUCUGCCAGCUUCUCUCGUUCCGUCGAUUGGGAGGAGCGGUGGCGACCUCGGCCUUCAGUGUUUCCGACGGAGUGAAUGGCGGCGGCGGCUGGGAUGCUGCUGCUGGGCUUGCUGCAGGCGGGUGGGUCGGUGCUGGGCCAGGCGAUGGAGAAGGUGACAGGCGGCAACCUCUUGUCCAUGCUGCUGAUCGCCUGCGCCUUCACCCUCAGCCUGGUCUACCUGAUCCGUCUGGCCGCCGGCCACCUGGUCCAGCUGCCCGCAGGGGUGAAAAGUCCUCCAUACAUUUUCUCCCCAAUUCCAUUCCUUGGGCAUGCCAUAGCAUUUGGGAAAAGUCCAAUUGAAUUUCUAGAAAAUGCAUAUGAGAAGUAUGGACCUGUAUUUAGUUUUACCAUGGUAGGCAAGACAUUUACUUACCUUCUGGGGAGUGAUGCUGCUGCACUGCUUUUUAAUAGUAAAAAUGAAGACCUGAAUGCAGAAGAUGUCUACAGUCGCCUGACAACACCUGUGUUUGGGAAGGGAGUUGCAUACGAUGUGCCUAAUCCAGUUUUCUUGGAGCAGAAGAAAAUGUUAAAAAGUGGCCUUAACAUAGCCCACUUUAAACAGCAUGUUUCUAUAAUUGAAAAAGAAACAAAGGAAUACUUUGAGAGUUGGGGAGAAAGUGGAGAAAAAAAUGUGUUUGAAGCUCUUUCUGAGCUCAUAAUUUUAACAGCUAGCCAUUGUUUGCAUGGAAAGGAAAUCAGAAGUCAACUCAAUGAAAAGGUAGCACAGCUGUAUGCAGAUUUGGAUGGAGGUUUCAGCCAUGCAGCCUGGCUCUUACCAGGUUGGCUGCCUUUGCCUAGUUUCAGACGCAGGGACAGAGCUCAUCGGGAAAUCAAGGAUAUUUUCUAUAAGGCAAUCCAGAAACGCAGACAGUCUCAAGAAAAAAUUGAUGACAUUCUCCAAACUUUACUAGAUGCUACAUACAAGGAUGGGCGUCCUUUGACUGAUGAUGAAGUAGCAGGGAUGCUUAUUGGAUUACUCUUGGCAGGGCAGCAUACAUCCUCAACUACUAGUGCUUGGAUGGGCUUCUUUUUGGCCAGAGACAAAACACUUCAAAAAAAAUGUUAUUUAGAACAGAAAACAGUCUGUGGAGAGAAUCUGCCUCCUUUAACUUAUGACCAGCUCAAGGAUCUAAAUUUACUUGAUCGCUGUAUAAAAGAAACAUUAAGACUUAGACCUCCUAUAAUGAUCAUGAUGAGAAUGGCCAGAACUCCUCAGACUGUGGCAGGGUAUACCAUUCCUCCAGGACAUCAGGUGUGUGUUUCUCCCACUGUCAAUCAAAGACUUAAAGACUCAUGGGUAGAACGCCUGGACUUUAAUCCUGAUCGCUACUUACAGGAUAACCCAGCAUCAGGGGAAAAGUUUGCCUAUGUGCCAUUUGGAGCUGGGCGUCAUCGUUGUAUUGGGGAAAAUUUUGCCUAUGUUCAAAUUAAGACAAUUUGGUCCACUAUGCUUCGUUUAUAUGAAUUUGAUCUCAUUGAUGGAUACUUUCCCACUGUGAAUUAUACAACUAUGAUUCACACCCCUGAAAACCCAGUUAUCCGUUACAAACGAAGAUCAAAAUGAAAAAGGUUGCAAGGAACGAAUAUAUGUGAUUAUCACUGUAAGCCACAAAGGCAUUCGAAGAGAAUGAAGUGUACAAAACAACUCUUGUAGUUUACUGUUUUUUUAAGUGUGUAAUUCUAAAAGCCAGUUUAUGAUUUAGGAUUUUGUUAACUGAAUGGUUCUAUCAAAUAUAAUAGCAUUUGAAACAUUUUCUAAUAGUUAUGAUACUUAUACAUGUGCUUUCAGGAAGUUCCUUGGUGAAACAAUUGUUGAGGGGGGAUCUAGGUAAUUGGCAGAUUCUAAAUAAUAUAAUUUCCAGAUAGUAAUUUUAAGAGUACUCAUCGCUCUUGCCAAAUAAGUUCAGGGUAUUCAAAUCUUGGACUAGUCCUGCAAGGUAUAAAGAAUAAAAAUCCCAGUGAGAUACUUGGAAACCACAGUUUAUUAUUAUUUAUCUGGGCAAUUAUUGUGUGUGUGAGGAUGGAAGGGUAGGGAAUAAUCGAACAUCUAAAGCCUUGAAUAAGAGAAUACUAAUUGUUUUGGUAUGAUGAUACUCAGAAAUGGAGAUAUUAUAGGAAAAAGAAAUCCUUUGGAAUUUUAACUAAAAUCACUGCAUAUGGGAAAUUAAGAGAUCCAGGACCAUAUUUGAUAAGAGUUCCUAAAAAUAAUGUAAUUAUUAAUGCUAAAGACUGCUCAUGUAUCUUGAUCUAAUUACUAAAUAAUUACAUAUUUAUUUACCUGAUAAAUAUGUAUCUAGUUCUACAAGGUCACAUUUAUGUGGAAGUCCAAAGUCAAGUCCUUAGGGGAUAAUUUUGUUUUGGCUCAGUUGUUCCCUGCUUCCUUUUUUUUUUUUUUUUUUUGAGAUGGAGUCUCGCUCUGUUGCCCAGGCUGGAGUGCAGUGGUGCGAUCUCAGCUCACUGCAUCCUCUGCCUCCCGGGUUCAAGCAAUUCUCUGCCUCAGCCUCCCAAGUAGUUGGGAUUACAGGCACCUGCCACCAUGCCUGGCUAAUUUUUUGUAUUUUUAGUAGAGACGGGGGUUUCACUAUGUUGGCUAGGCUGGUCUUGAACUCCUGACCUCGUGAUCCACCCGCCUUGGCCUCCCAAAGUGCUGGGAUUACAGGCAUGAGCCACCGCACCUGGCCUUCCCUGCUUCCUCUCUAGAAUCCAAUUAGGGAUGUUUGUUACUACUCAUAUUGAUUAAAACAGUUAACAAACUUUUUUCUUUUUAAAAUGUGAGAUCAGUGAACUCUGGUUUUAAGAUAAUCUGAAACAAGGUCCUUGGGAGUAAUAAAAUUGGUCACAUUCUGUAAAGCACAUUCUGUUUAGGAAUCAACUUAUCUCAAAUUGUAACUCGGGGCCUAACUAUAUGAGAUGGCUGAAAAAAUACCACAUCGUCUGUUUUCACUAGGUGAUGCCAAAAUAUUUUGCUUUAUGUAUAUUACAGUUCUUUUUAAAACACUGGAAGACUCAUGUUAAACUCUAAUUGUGAAGGCAGAAUCUCUGCUAAUUUUUCAGAUUAAAAUUCUCUUUGAAAAAAUACA

The terms “cytochrome P450 isoform 51A1,” “CYP51A1,” and “lanosterol14-alpha demethylase” as used herein include, for example, forms of thehuman CYP51A1 protein that have an amino acid sequence that is at least85% identical to the amino acid sequence of SEQ ID NO: 1 (e.g., 85%,86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%,99.9%, or 100% identical to the amino acid sequence of SEQ ID NO: 1)and/or forms of the human CYP51A1 protein that contain one or moresubstitutions, insertions, and/or deletions (e.g., one or moreconservative and/or nonconservative amino acid substitutions, such as upto 5, 10, 15, 20, 25, or more, conservative or nonconservative aminoacid substitutions) relative to a wild-type CYP51A1 protein. Similarly,the terms “cytochrome P450 isoform 51A1,” “CYP51A1,” and “lanosterol14-alpha demethylase” as used herein include, for example, forms of thehuman CYP51A1 gene that encode an mRNA transcript having a nucleic acidsequence that is at least 85% identical to the nucleic acid sequence ofSEQ ID NO: 2 (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%,95%, 96%, 97%, 98%, 99%, 99.9%, or 100% identical to the amino acidsequence of SEQ ID NO: 2).

As used herein, the terms “cytochrome P450 isoform 51A1 inhibitor,”“CYP51A1 inhibitor,” and “lanosterol 14-alpha demethylase inhibitor” areused interchangeably and refer to substances, such as small molecules,peptides, and biologic agents (e.g., antibodies and antigen-bindingfragments thereof), that suppress the activity of the CYP51A1 enzyme.Inhibitors of this type may, for example, competitively inhibit CYP51A1activity by specifically binding the CYP51A1 enzyme (e.g., by virtue ofthe affinity of the inhibitor for the CYP51A1 active site), therebyprecluding, hindering, or halting the entry of one or more endogenoussubstrates of CYP51A1 into the enzyme's active site. Additional examplesof CYP51A1 inhibitors that suppress the activity of the CYP51A1 enzymeinclude substances, such as small molecules, peptides, and biologicagents (e.g., antibodies and antigen-binding fragments thereof), thatmay bind CYP51A1 at a site distal from the active site and attenuate thebinding of endogenous substrates to the CYP51A1 active site by way of achange in the enzyme's spatial conformation upon binding of theinhibitor. In addition to encompassing substances that modulate CYP51A1activity, the terms “cytochrome P450 isoform 51A1 inhibitor,” “CYP51A1inhibitor,” and “lanosterol 14-alpha demethylase inhibitor” refer tosubstances that reduce the concentration and/or stability of CYP51A1mRNA transcripts in vivo, as well as those that suppress the translationof functional CYP51A1 enzyme. Examples of inhibitors of this type areinterfering RNA molecules, such as short interfering RNA (siRNA), microRNA (miRNA), and short hairpin RNA (shRNA). Additional examples of“cytochrome P450 isoform 51A1 inhibitors,” “CYP51A1 inhibitors,” and“lanosterol 14-alpha demethylase inhibitors” are substances, such assmall molecules, peptides, and biologic agents (e.g., antibodies andantigen-binding fragments thereof), that attenuate the transcription ofan endogenous gene encoding CYP51A1.

As used herein, the term “dose” refers to the quantity of a therapeuticagent, such as a CYP51A1 inhibitor described herein (e.g., an inhibitorysmall molecule, antibody, antigen-binding fragment thereof, orinterfering RNA molecule described herein) that is administered to asubject for the treatment of a disorder or condition, such as to treator prevent a neurological disorder in a subject (e.g., a human subject).A therapeutic agent as described herein may be administered in a singledose or in multiple doses for the treatment of a particular indication.In each case, the therapeutic agent may be administered using one ormore unit dosage forms of the therapeutic agent. For instance, a singledose of 1 mg of a therapeutic agent may be administered using, e.g., two0.5 mg unit dosage forms of the therapeutic agent, four 0.25 mg unitdosage forms of the therapeutic agent, one single 1 mg unit dosage formof the therapeutic agent, and the like.

As used herein, the term “endogenous” describes a molecule (e.g., ametabolite, polypeptide, nucleic acid, or cofactor) that is foundnaturally in a particular organism (e.g., a human) or in a particularlocation within an organism (e.g., an organ, a tissue, or a cell, suchas a human cell).

As used herein, the term “exogenous” describes a molecule (e.g., a smallmolecule, polypeptide, nucleic acid, or cofactor) that is not foundnaturally in a particular organism (e.g., a human) or in a particularlocation within an organism (e.g., an organ, a tissue, or a cell, suchas a human cell). Exogenous materials include those that are providedfrom an external source to an organism or to cultured matter extractedthere from.

As used herein, the term “interfering RNA” refers to a RNA, such as ashort interfering RNA (siRNA), micro RNA (miRNA), or short hairpin RNA(shRNA) that suppresses the expression of a target RNA transcript, forexample, by way of (i) annealing to the target RNA transcript, therebyforming a nucleic acid duplex; and (ii) promoting the nuclease-mediateddegradation of the RNA transcript and/or (iii) slowing, inhibiting, orpreventing the translation of the RNA transcript, such as by stericallyprecluding the formation of a functional ribosome-RNA transcript complexor otherwise attenuating formation of a functional protein product fromthe target RNA transcript. Interfering RNAs as described herein may beprovided to a patient, such as a human patient having a neurologicaldisorder described herein, in the form of, for example, a single- ordouble-stranded oligonucleotide, or in the form of a vector (e.g., aviral vector) containing a transgene encoding the interfering RNA.Exemplary interfering RNA platforms are described, for example, in Lamet al., Molecular Therapy-Nucleic Acids 4:e252 (2015); Rao et al.,Advanced Drug Delivery Reviews 61:746-769 (2009); and Borel et al.,Molecular Therapy 22:692-701 (2014), the disclosures of each of whichare incorporated herein by reference in their entirety.

“Percent (%) sequence complementarity” with respect to a referencepolynucleotide sequence is defined as the percentage of nucleic acids ina candidate sequence that are complementary to the nucleic acids in thereference polynucleotide sequence, after aligning the sequences andintroducing gaps, if necessary, to achieve the maximum percent sequencecomplementarity. A given nucleotide is considered to be “complementary”to a reference nucleotide as described herein if the two nucleotidesform canonical Watson-Crick base pairs. For the avoidance of doubt,Watson-Crick base pairs in the context of the present disclosure includeadenine-thymine, adenine-uracil, and cytosine-guanine base pairs. Aproper Watson-Crick base pair is referred to in this context as a“match,” while each unpaired nucleotide, and each incorrectly pairednucleotide, is referred to as a “mismatch.” Alignment for purposes ofdetermining percent nucleic acid sequence complementarity can beachieved in various ways that are within the capabilities of one ofskill in the art, for example, using publicly available computersoftware such as BLAST, BLAST-2, or Megalign software. Those skilled inthe art can determine appropriate parameters for aligning sequences,including any algorithms needed to achieve maximal complementarity overthe full length of the sequences being compared. As an illustration, thepercent sequence complementarity of a given nucleic acid sequence, A, toa given nucleic acid sequence, B, (which can alternatively be phrased asa given nucleic acid sequence, A that has a certain percentcomplementarity to a given nucleic acid sequence, B) is calculated asfollows:100 multiplied by (the fraction X/Y)where X is the number of complementary base pairs in an alignment (e.g.,as executed by computer software, such as BLAST) in that program'salignment of A and B, and where Y is the total number of nucleic acidsin B. It will be appreciated that where the length of nucleic acidsequence A is not equal to the length of nucleic acid sequence B, thepercent sequence complementarity of A to B will not equal the percentsequence complementarity of B to A. As used herein, a query nucleic acidsequence is considered to be “completely complementary” to a referencenucleic acid sequence if the query nucleic acid sequence has 100%sequence complementarity to the reference nucleic acid sequence.

“Percent (%) sequence identity” with respect to a referencepolynucleotide or polypeptide sequence is defined as the percentage ofnucleic acids or amino acids in a candidate sequence that are identicalto the nucleic acids or amino acids in the reference polynucleotide orpolypeptide sequence, after aligning the sequences and introducing gaps,if necessary, to achieve the maximum percent sequence identity.Alignment for purposes of determining percent nucleic acid or amino acidsequence identity can be achieved in various ways that are within thecapabilities of one of skill in the art, for example, using publiclyavailable computer software such as BLAST, BLAST-2, or Megalignsoftware. Those skilled in the art can determine appropriate parametersfor aligning sequences, including any algorithms needed to achievemaximal alignment over the full length of the sequences being compared.For example, percent sequence identity values may be generated using thesequence comparison computer program BLAST. As an illustration, thepercent sequence identity of a given nucleic acid or amino acidsequence, A, to, with, or against a given nucleic acid or amino acidsequence, B, (which can alternatively be phrased as a given nucleic acidor amino acid sequence, A that has a certain percent sequence identityto, with, or against a given nucleic acid or amino acid sequence, B) iscalculated as follows:100 multiplied by (the fraction X/Y)where X is the number of nucleotides or amino acids scored as identicalmatches by a sequence alignment program (e.g., BLAST) in that program'salignment of A and B, and where Y is the total number of nucleic acidsin B. It will be appreciated that where the length of nucleic acid oramino acid sequence

A is not equal to the length of nucleic acid or amino acid sequence B,the percent sequence identity of A to B will not equal the percentsequence identity of B to A.

As used herein in the context of administration of a therapeutic agent,the term “periodically” refers to administration of the agent two ormore times over the course of a treatment period (e.g., two or moretimes daily, weekly, monthly, or yearly).

As used herein, the term “pharmaceutical composition” means a mixturecontaining a therapeutic compound to be administered to a patient, suchas a mammal, e.g., a human, in order to prevent, treat or control aparticular disease or condition affecting the mammal, such as aneurological disorder described herein.

As used herein, the term “pharmaceutically acceptable” refers to thosecompounds, materials, compositions and/or dosage forms, which aresuitable for contact with the tissues of a patient, such as a mammal(e.g., a human) without excessive toxicity, irritation, allergicresponse and other problem complications commensurate with a reasonablebenefit/risk ratio.

As used herein in the context of therapeutic treatment, the terms“provide” and “providing” refer to the delivery of a therapeutic agentto a subject (e.g., a mammalian subject, such as a human) in need oftreatment, such as a subject experiencing or at risk of developing aneurological disorder described herein. A therapeutic agent may beprovided to a subject in need thereof, for instance, by directadministration of the therapeutic agent to the subject, or byadministration of a prodrug that is converted in vivo to the therapeuticagent upon administration of the prodrug to the subject. Exemplaryprodrugs include, without limitation, esters, phosphates, and otherchemical functionalities susceptible to hydrolysis upon administrationto a subject. Prodrugs include those known in the art, such as thosedescribed, for instance, in Vig et al., Adv. Drug Deliv. Rev.65:1370-1385 (2013), and Huttunen et al., Pharmacol. Rev. 63:750-771(2011), the disclosures of each of which are incorporated herein byreference in their entirety.

As used herein, the term “neuromuscular disorder” refers to a diseaseimpairing the ability of one or more neurons to control the activity ofan associated muscle. Examples of neuromuscular disorders areamyotrophic lateral sclerosis, congenital myasthenic syndrome,congenital myopathy, cramp fasciculation syndrome, Duchenne musculardystrophy, glycogen storage disease type II, hereditary spasticparaplegia, inclusion body myositis, Isaac's Syndrome, Kearns-Sayresyndrome, Lambert-Eaton myasthenic syndrome, mitochondrial myopathy,muscular dystrophy, myasthenia gravis, myotonic dystrophy, peripheralneuropathy, spinal and bulbar muscular atrophy, spinal muscular atrophy,Stiff person syndrome, Troyer syndrome, and Guillain-Barré syndrome,among others.

As used herein, the term “sample” refers to a specimen (e.g., blood,blood component (e.g., serum or plasma), urine, saliva, amniotic fluid,cerebrospinal fluid, tissue (e.g., placental or myometrial), pancreaticfluid, chorionic villus sample, and cells) isolated from a patient.

As used herein, the phrases “specifically binds” and “binds” refer to abinding reaction which is determinative of the presence of a particularprotein in a heterogeneous population of proteins and other biologicalmolecules that is recognized, e.g., by a ligand with particularity. Aligand (e.g., a protein, proteoglycan, or glycosaminoglycan) thatspecifically binds to a protein will bind to the protein, e.g., with aK_(D) of less than 100 nM. For example, a ligand that specifically bindsto a protein may bind to the protein with a K_(D) of up to 100 nM (e.g.,between 1 pM and 100 nM). A ligand that does not exhibit specificbinding to a protein or a domain thereof will exhibit a K_(D) of greaterthan 100 nM (e.g., greater than 200 nM, 300 nM, 400 nM, 500 nM, 600 nm,700 nM, 800 nM, 900 nM, 1 μM, 100 μM, 500 μM, or 1 mM) for thatparticular protein or domain thereof. A variety of assay formats may beused to determine the affinity of a ligand for a specific protein. Forexample, solid-phase ELISA assays are routinely used to identify ligandsthat specifically bind a target protein. See, e.g., Harlow & Lane,Antibodies, A Laboratory Manual, Cold Spring Harbor Press, New York(1988) and Harlow & Lane, Using Antibodies, A Laboratory Manual, ColdSpring Harbor Press, New York (1999), for a description of assay formatsand conditions that can be used to determine specific protein binding.

As used herein, the terms “subject’ and “patient” are usedinterchangeably and refer to an organism, such as a mammal (e.g., ahuman) that receives therapy for the treatment or prevention of aneurological disease described herein, for example, for amyotrophiclateral sclerosis. Patients that may receive therapy, or that areconsidered to be in need of therapy, for the treatment or prevention ofa neurological disease described herein include subjects (e.g., humansubjects) that have been diagnosed as having the neurological diseaseand/or that exhibit one or more symptoms of the disease, as well asthose at risk of developing the disease. In the context of aneurological disorder described herein, such as amyotrophic lateralsclerosis, examples of patients that may be treated using thecompositions and methods of the present disclosure are those that are atrisk of developing the disease, as well as those that are classified ashaving clinically definite, clinically probable, clinically probable(laboratory-supported), or clinically possible amyotrophic lateralsclerosis according to the EI-Escorial diagnostic criteria for thisdisease. A patient may be diagnosed as having a neurological disorder,for example, by way of (i) electrodiagnostic tests includingelectomyography (EMG) and nerve conduction velocity (NCV); (ii) bloodand urine studies, including high resolution serum proteinelectrophoresis, thyroid and parathyroid hormone levels, and 24-hoururine collection for heavy metals; (iii) spinal tap; x-rays, includingmagnetic resonance imaging; (iv) myelogram of cervical spine; (v) muscleand/or nerve biopsy; and/or (vi) thorough neurological evaluation.

A variety of clinical indicators can be used to identify a patient as“at risk” of developing a particular neurological disease. Examples ofpatients (e.g., human patients) that are “at risk” of developing aneurological disease, such as amyotrophic lateral sclerosis,frontotemporal degeneration, Alzheimer's disease, Parkinson's disease,dementia with Lewy Bodies, corticobasal degeneration, progressivesupranuclear palsy, dementia parkinsonism ALS complex of Guam,Huntington's disease, Inclusion body myopathy with early-onset Pagetdisease and frontotemporal dementia (IBMPFD), sporadic inclusion bodymyositis, myofibrillar myopathy, dementia pugilistica, chronic traumaticencephalopathy, Alexander disease, and hereditary inclusion bodymyopathy, include (i) subjects exhibiting or prone to exhibitaggregation of TAR-DNA binding protein (TDP)-43, and (ii) subjectsexpressing a mutant form of TDP-43 containing a mutation associated withTDP-43 aggregation and toxicity, such as a mutation selected from Q331K,M337V, Q343R, N345K, R361 S, and N390D. Subjects that are “at risk” ofdeveloping amyotrophic lateral sclerosis may exhibit one or both ofthese characteristics, for example, prior to the first administration ofa CYP51A1 inhibitor in accordance with the compositions and methodsdescribed herein.

As used herein, the terms “TAR-DNA binding protein-43” and “TDP-43” areused interchangeably and refer to the transcription repressor proteininvolved in modulating HIV-1 transcription and alternative splicing ofthe cystic fibrosis transmembrane conductance regulator (CFTR) pre-mRNAtranscript, for example, in human subjects. The terms “TAR-DNA bindingprotein-43” and “TDP-43” refer not only to wild-type forms of TDP-43,but also to variants of wild-type TDP-43 proteins and nucleic acidsencoding the same. The amino acid sequence and corresponding mRNAsequence of a wild-type form of human TDP-43 are provided herein as SEQID NOs: 3 and 4, which correspond to NCBI Reference Sequence NOs.NM_007375.3 and NP_031401.1, respectively. These sequences are shown inTable 3, below.

TABLE 3 Amino acid and nucleic acid sequences of wild-type human TDP-43SEQ ID NO. Sequence 3MSEYIRVTEDENDEPIEIPSEDDGTVLLSTVTAQFPGACGLRYRNPVSQCMRGVRLVEGILHAPDAGWGNLVYVVNYPKDNKRKMDETDASSAVKVKRAVQKTSDLIVLGLPWKTTEQDLKEYFSTFGEVLMVQVKKDLKTGHSKGFGFVRFTEYETQVKVMSQRHMIDGRWCDCKLPNSKQSQDEPLRSRKVFVGRCTEDMTEDELREFFSQYGDVMDVFIPKPFRAFAFVTFADDQIAQSLCGEDLIIKGISVHISNAEPKHNSNRQLERSGRFGGNPGGFGNQGGFGNSRGGGAGLGNNQGSNMGGGMNFGAFSINPAMMAAAQAALQSSWGMMGMLASQQNQSGPSGNNQNQGNMQREPNQAFGSGNNSYSGSNSGAAIGWGSASNAGSGSGFNGGFGSSMDSKSSGWGM 4GGUGGGCGGGGGGAGGAGGCGGCCCUAGCGCCAUUUUGUGGGAGCGAAGCGGUGGCUGGGCUGCGCUUGGGUCCGUCGCUGCUUCGGUGUCCCUGUCGGGCUUCCCAGCAGCGGCCUAGCGGGAAAAGUAAAAGAUGUCUGAAUAUAUUCGGGUAACCGAAGAUGAGAACGAUGAGCCCAUUGAAAUACCAUCGGAAGACGAUGGGACGGUGCUGCUCUCCACGGUUACAGCCCAGUUUCCAGGGGCGUGUGGGCUUCGCUACAGGAAUCCAGUGUCUCAGUGUAUGAGAGGUGUCCGGCUGGUAGAAGGAAUUCUGCAUGCCCCAGAUGCUGGCUGGGGAAAUCUGGUGUAUGUUGUCAACUAUCCAAAAGAUAACAAAAGAAAAAUGGAUGAGACAGAUGCUUCAUCAGCAGUGAAAGUGAAAAGAGCAGUCCAGAAAACAUCCGAUUUAAUAGUGUUGGGUCUCCCAUGGAAAACAACCGAACAGGACCUGAAAGAGUAUUUUAGUACCUUUGGAGAAGUUCUUAUGGUGCAGGUCAAGAAAGAUCUUAAGACUGGUCAUUCAAAGGGGUUUGGCUUUGUUCGUUUUACGGAAUAUGAAACACAAGUGAAAGUAAUGUCACAGCGACAUAUGAUAGAUGGACGAUGGUGUGACUGCAAACUUCCUAAUUCUAAGCAAAGCCAAGAUGAGCCUUUGAGAAGCAGAAAAGUGUUUGUGGGGCGCUGUACAGAGGACAUGACUGAGGAUGAGCUGCGGGAGUUCUUCUCUCAGUACGGGGAUGUGAUGGAUGUCUUCAUCCCCAAGCCAUUCAGGGCCUUUGCCUUUGUUACAUUUGCAGAUGAUCAGAUUGCGCAGUCUCUUUGUGGAGAGGACUUGAUCAUUAAAGGAAUCAGCGUUCAUAUAUCCAAUGCCGAACCUAAGCACAAUAGCAAUAGACAGUUAGAAAGAAGUGGAAGAUUUGGUGGUAAUCCAGGUGGCUUUGGGAAUCAGGGUGGAUUUGGUAAUAGCAGAGGGGGUGGAGCUGGUUUGGGAAACAAUCAAGGUAGUAAUAUGGGUGGUGGGAUGAACUUUGGUGCGUUCAGCAUUAAUCCAGCCAUGAUGGCUGCCGCCCAGGCAGCACUACAGAGCAGUUGGGGUAUGAUGGGCAUGUUAGCCAGCCAGCAGAACCAGUCAGGCCCAUCGGGUAAUAACCAAAACCAAGGCAACAUGCAGAGGGAGCCAAACCAGGCCUUCGGUUCUGGAAAUAACUCUUAUAGUGGCUCUAAUUCUGGUGCAGCAAUUGGUUGGGGAUCAGCAUCCAAUGCAGGGUCGGGCAGUGGUUUUAAUGGAGGCUUUGGCUCAAGCAUGGAUUCUAAGUCUUCUGGCUGGGGAAUGUAGACAGUGGGGUUGUGGUUGGUUGGUAUAGAAUGGUGGGAAUUCAAAUUUUUCUAAACUCAUGGUAAGUAUAUUGUAAAAUACAUAUGUACUAAGAAUUUUCAAAAUUGGUUUGUUCAGUGUGGAGUAUAUUCAGCAGUAUUUUUGACAUUUUUCUUUAGAAAAAGGAAGAGCUAAAGGAAUUUUAUAAGUUUUGUUACAUGAAAGGUUGAAAUAUUGAGUGGUUGAAAGUGAACUGCUGUUUGCCUGAUUGGUAAACCAACACACUACAAUUGAUAUCAAAAGGUUUCUCCUGUAAUAUUUUAUCCCUGGACUUGUCAAGUGAAUUCUUUGCAUGUUCAAAACGGAAACCAUUGAUUAGAACUACAUUCUUUACCCCUUGUUUUAAUUUGAACCCCACCAUAUGGAUUUUUUUCCUUAAGAAAAUCUCCUUUUAGGAGAUCAUGGUGUCACAGUGUUUGGUUCUUUUGUUUUGUUUUUUAACACUUGUCUCCCCUCAUACACAAAAGUACAAUAUGAAGCCUUCAUUUAAUCUCUGCAGUUCAUCUCAUUUCAAAUGUUUAUGGAAGAAGCACUUCAUUGAAAGUAGUGCUGUAAAUAUUCUGCCAUAGGAAUACUGUCUACAUGCUUUCUCAUUCAAGAAUUCGUCAUCACGCAUCACAGGCCGCGUCUUUGACGGUGGGUGUCCCAUUUUUAUCCGCUACUCUUUAUUUCAUGGAGUCGUAUCAACGCUAUGAACGCAAGGCUGUGAUAUGGAACCAGAAGGCUGUCUGAACUUUUGAAACCUUGUGUGGGAUUGAUGGUGGUGCCGAGGCAUGAAAGGCUAGUAUGAGCGAGAAAAGGAGAGAGCGCGUGCAGAGACUUGGUGGUGCAUAAUGGAUAUUUUUUAACUUGGCGAGAUGUGUCUCUCAAUCCUGUGGCUUUGGUGAGAGAGUGUGCAGAGAGCAAUGAUAGCAAAUAAUGUACGAAUGUUUUUUGCAUUCAAAGGACAUCCACAUCUGUUGGAAGACUUUUAAGUGAGUUUUUGUUCUUAGAUAACCCACAUUAGAUGAAUGUGUUAAGUGAAAUGAUACUUGUACUCCCCCUACCCCUUUGUCAACUGCUGUGAAUGCUGUAUGGUGUGUGUUCUCUUCUGUUACUGAUAUGUAAGUGUGGCAAUGUGAACUGAAGCUGAUGGGCUGAGAACAUGGACUGAGCUUGUGGUGUGCUUUGCAGGAGGACUUGAAGCAGAGUUCACCAGUGAGCUCAGGUGUCUCAAAGAAGGGUGGAAGUUCUAAUGUCUGUUAGCUACCCAUAAGAAUGCUGUUUGCUGCAGUUCUGUGUCCUGUGCUUGGAUGCUUUUUAUAAGAGUUGUCAUUGUUGGAAAUUCUUAAAUAAAACUGAUUUAAAUAAUAUGUGUCUUUGUUUUGCAGCCCUGAAUGCAAAGAAUUCAUAGCAGUUAAUUCCCCUUUUUUGACCCUUUUGAGAUGGAACUUUCAUAAAGUUUCUUGGCAGUAGUUUAUUUUGCUUCAAAUAAACUUAUUUGAAAAGUUGUCUCAAGUCAAAUGGAUUCAUCACCUGUCAUGCAUUGACACCUGAUACCCAGACUUAAUUGGUAUUUGUUCUUGCAUUGGCCAAAGUGAAAAUUUUUUUUUUUCUUUUGAAAUCUAGUUUUGAAUAAGUCUGGGUGACCGCACCUAAAAUGGUAAGCAGUACCCUCCGGCUUUUUCUUAGUGCCUCUGUGCAUUUGGGUGAUGUUCUAUUUACAUGGCCUGUGUAAAUCUCCAUUGGGAAGUCAUGCCUUCUAAAAAGAUUCUUAUUUGGGGGAGUGGGCAAAAUGUUGAUUAUUUUCUAAUGCUUUGUAGCAAAGCAUAUCAAUUGAAAAGGGAAUAUCAGCACCUUCCUAGUUUGGGAUUUGAAAAGUGGAAUUAAUUGCAGUAGGGAUAAAGUAGAAGAAACCACAAAUUAUCUUGUGCCUGAAAUCCAUUAAGAGGCCUGAUAGCUUUAAGAAUUAGGGUGGGUUGUCUGUCUGGAAGUGUUAAGUGGAAUGGGCUUUGUCCUCCAGGAGGUGGGGGAAUGUGGUAACAUUGAAUACAGUUGAAUAAAAUCGCUUACAAAACUCACACUCUCACAAUGCAUUGUUAAGUAUGUAAAAGCAAUAACAUUGAUUCUCUGUUGUACUUUUUUGUAACUAAUUCUGUGAGAGUUGAGCUCAUUUUCUAGUUGGAAGAAUGUGAUAUUUGUUGUGUUGGUAGUUUACCUAAUGCCCUUACCUAAUUAGAUUAUGAUAAAUAGGUUUGUCAUUUUGCAAGUUACAUAAACAUUUAUCAAUGAAGUCAUCCUUUAGACUUGUAAUCGCCACAUUGUUUCAUUAUUCAGUUUCCUCUGUAAAGGGAUCUUGAGUUGUUUUAAUUUUUUUUUUCUGCAUCUGAAUCUGCAUGAUUUCCAAACCCUGUACCAUCUGAAUUUUGCAUUUUAGCACUUGCACUAUUACUCAGCAGCAGUAACAUGGUAACACUUAAAAUGGUACUCGGGGACCUCCAAAGACUAAACUGACAAGCCUUCAAGGAGCCCAGGGGUAAGUUAACUUGUCAACGGCAUGGUUUAAUCCCUUCUUUACACUUGUGUAAAUUUCAGUUACUGGUCAUAGAAGGCUUUCAAUGUUGAGUGGCCUUUUAUUAACAUGUUUAUGGUACUGCAUAGAUACGGGUAUUUAUUUUACCCUAAGAAGAUUUUGAAGUUUAAAAGUACUUAAACUAUUUGGCAAAGAUUUGUUUUUAAAAAUCUAUUUGGUCAAUCUAAAUGCAUUCAUUCUAAAAAAUUUUUUGAACCAGAUAAAUAAAAUUUUUUUUUGACACCACAAAAAAAAAAAAAAAAAAAA

The terms “TAR-DNA binding protein-43” and “TDP-43” as used hereininclude, for example, forms of the human TDP-43 protein that have anamino acid sequence that is at least 85% identical to the amino acidsequence of SEQ ID NO: 3 (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9%, or 100% identical to the aminoacid sequence of SEQ ID NO: 3) and/or forms of the human TDP-43 proteinthat contain one or more substitutions, insertions, and/or deletions(e.g., one or more conservative and/or nonconservative amino acidsubstitutions, such as up to 5, 10, 15, 20, 25, or more, conservative ornonconservative amino acid substitutions) relative to a wild-type TDP-43protein. For instance, patients that may be treated for a neurologicaldisorder as described herein, such as amyotrophic lateral sclerosis,frontotemporal degeneration, Alzheimer's disease, Parkinson's disease,dementia with Lewy Bodies, corticobasal degeneration, progressivesupranuclear palsy, dementia parkinsonism ALS complex of Guam,Huntington's disease, Inclusion body myopathy with early-onset Pagetdisease and frontotemporal dementia (IBMPFD), sporadic inclusion bodymyositis, myofibrillar myopathy, dementia pugilistica, chronic traumaticencephalopathy, Alexander disease, and hereditary inclusion bodymyopathy, include human patients that express a form of TDP-43 having amutation associated with elevated TDP-43 aggregation and toxicity, suchas a mutation selected from Q331K, M337V, Q343R, N345K, R361S, andN390D. Similarly, the terms “TAR-DNA binding protein-43” and “TDP-43” asused herein include, for example, forms of the human TDP-43 gene thatencode an mRNA transcript having a nucleic acid sequence that is atleast 85% identical to the nucleic acid sequence of SEQ ID NO: 4 (e.g.,85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%,99%, 99.9%, or 100% identical to the amino acid sequence of SEQ ID NO:4).

As used herein in the context of a CYP51A1 inhibitor, such as aninhibitory small molecule, antibody, antigen-binding fragment thereof,or interfering RNA molecule described herein, the term “therapeuticallyeffective amount” refers to a quantity of the inhibitor that, optionallywhen administered in combination with one another agent, achieves abeneficial treatment outcome for a subject that has or is at risk ofdeveloping a neurological disease described herein, such as amyotrophiclateral sclerosis, frontotemporal degeneration, Alzheimer's disease,Parkinson's disease, dementia with Lewy Bodies, corticobasaldegeneration, progressive supranuclear palsy, dementia parkinsonism ALScomplex of Guam, Huntington's disease, Inclusion body myopathy withearly-onset Paget disease and frontotemporal dementia (IBMPFD), sporadicinclusion body myositis, myofibrillar myopathy, dementia pugilistica,chronic traumatic encephalopathy, Alexander disease, and hereditaryinclusion body myopathy. For example, the term “therapeuticallyeffective amount” of a CYP51A1 inhibitor described herein includesamounts of the inhibitor that, optionally when administered incombination with another agent, is capable of achieving (i) animprovement in the subject's condition as assessed using the amyotrophiclateral sclerosis functional rating scale (ALSFRS) or the revised ALSFRS(ALSFRS-R) following administration of the CYP51A1 inhibitor, such as animprovement in the subject's ALSFRS or ALSFRS-R score within one or moredays, weeks, or months following administration of the CYP51A1 inhibitor(e.g., an improvement in the subject's ALSFRS or ALSFRS-R score withinfrom about 1 day to about 48 weeks (e.g., within from about 2 days toabout 36 weeks, from about 4 weeks to about 24 weeks, from about 8 weeksto about 20 weeks, or from about 12 weeks to about 16 weeks), or more,following the initial administration of the CYP51A1 inhibitor to thesubject, such as within 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7days, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44weeks, 45 weeks, 46 weeks, 47 weeks, 48 weeks, or more, following theinitial administration of the CYP51A1 inhibitor to the subject); (ii) anincrease in the subject's slow vital capacity following administrationof the CYP51A1 inhibitor, such as an increase in the subject's slowvital capacity within one or more days, weeks, or months followingadministration of the CYP51A1 inhibitor (e.g., an increase in thesubject's slow vital capacity within from about 1 day to about 48 weeks(e.g., within from about 2 days to about 36 weeks, from about 4 weeks toabout 24 weeks, from about 8 weeks to about 20 weeks, or from about 12weeks to about 16 weeks), or more, following the initial administrationof the CYP51A1 inhibitor to the subject, such as within 1 day, 2 days, 3days, 4 days, 5 days, 6 days, 7 days, 2 weeks, 3 weeks, 4 weeks, 5weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks,13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48weeks, or more, following the initial administration of the CYP51A1inhibitor to the subject); (iii) a reduction in decremental responsesexhibited by the subject upon repetitive nerve stimulation, such as areduction that is observed within one or more days, weeks, or monthsfollowing administration of the CYP51A1 inhibitor (e.g., a reductionthat is observed within from about 1 day to about 48 weeks (e.g., withinfrom about 2 days to about 36 weeks, from about 4 weeks to about 24weeks, from about 8 weeks to about 20 weeks, or from about 12 weeks toabout 16 weeks), or more, following the initial administration of theCYP51A1 inhibitor to the subject, such as within 1 day, 2 days, 3 days,4 days, 5 days, 6 days, 7 days, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48weeks, or more, following the initial administration of the CYP51A1inhibitor to the subject); (iv) an improvement in the subject's musclestrength, as assessed, for example, by way of the Medical ResearchCouncil muscle testing scale (as described, e.g., in Jagtap et al., Ann.Indian. Acad. Neurol. 17:336-339 (2014), the disclosure of which isincorporated herein by reference as it pertains to measuring patientresponse to neurological disease treatment), such as an improvement thatis observed within one or more days, weeks, or months followingadministration of the CYP51A1 inhibitor (e.g., an improvement that isobserved within from about 1 day to about 48 weeks (e.g., within fromabout 2 days to about 36 weeks, from about 4 weeks to about 24 weeks,from about 8 weeks to about 20 weeks, or from about 12 weeks to about 16weeks), or more, following the initial administration of the CYP51A1inhibitor to the subject, such as within 1 day, 2 days, 3 days, 4 days,5 days, 6 days, 7 days, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 weeks, ormore, following the initial administration of the CYP51A1 inhibitor tothe subject); (v) an improvement in the subject's quality of life, asassessed, for example, using the amyotrophic lateral sclerosis-specificquality of life (ALS-specific QOL) questionnaire, such as an improvementin the subject's quality of life that is observed within one or moredays, weeks, or months following administration of the CYP51A1 inhibitor(e.g., an improvement in the subject's quality of life that is observedwithin from about 1 day to about 48 weeks (e.g., within from about 2days to about 36 weeks, from about 4 weeks to about 24 weeks, from about8 weeks to about 20 weeks, or from about 12 weeks to about 16 weeks), ormore, following the initial administration of the CYP51A1 inhibitor tothe subject, such as within 1 day, 2 days, 3 days, 4 days, 5 days, 6days, 7 days, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 weeks, or more,following the initial administration of the CYP51A1 inhibitor to thesubject); and/or (vi) a decrease in the frequency and/or severity ofmuscle cramps exhibited by the subject, such as a decrease in crampfrequency and/or severity within one or more days, weeks, or monthsfollowing administration of the CYP51A1 inhibitor (e.g., a decrease incramp frequency and/or severity within from about 1 day to about 48weeks (e.g., within from about 2 days to about 36 weeks, from about 4weeks to about 24 weeks, from about 8 weeks to about 20 weeks, or fromabout 12 weeks to about 16 weeks), or more, following the initialadministration of the CYP51A1 inhibitor to the subject, such as within 1day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 2 weeks, 3 weeks, 4weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks,12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47weeks, 48 weeks, or more, following the initial administration of theCYP51A1 inhibitor to the subject).

As used herein in the context of a neurological disorder, the terms“treat” or “treatment” refer to therapeutic treatment, in which theobject is to slow, delay, or halt the progression or development of aneurological disorder, e.g., in a human subject. Successful treatment ofa subject using a CYP51A1 inhibitor as described herein (e.g., using aCYP51A1 inhibitory small molecule, antibody, antigen-binding fragmentthereof, or interfering RNA molecule described herein) may manifest in avariety of ways. Desired treatment outcomes that may be achieved usingthe compositions and methods described herein include, withoutlimitation, (i) an improvement in the subject's condition as assessedusing the amyotrophic lateral sclerosis functional rating scale (ALSFRS)or the revised ALSFRS (ALSFRS-R) following administration of the CYP51A1inhibitor, such as an improvement in the subject's ALSFRS or ALSFRS-Rscore within one or more days, weeks, or months following administrationof the CYP51A1 inhibitor (e.g., an improvement in the subject's ALSFRSor ALSFRS-R score within from about 1 day to about 48 weeks (e.g.,within from about 2 days to about 36 weeks, from about 4 weeks to about24 weeks, from about 8 weeks to about 20 weeks, or from about 12 weeksto about 16 weeks), or more, following the initial administration of theCYP51A1 inhibitor to the subject, such as within 1 day, 2 days, 3 days,4 days, 5 days, 6 days, 7 days, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48weeks, or more, following the initial administration of the CYP51A1inhibitor to the subject); (ii) an increase in the subject's slow vitalcapacity following administration of the CYP51A1 inhibitor, such as anincrease in the subject's slow vital capacity within one or more days,weeks, or months following administration of the CYP51A1 inhibitor(e.g., an increase in the subject's slow vital capacity within fromabout 1 day to about 48 weeks (e.g., within from about 2 days to about36 weeks, from about 4 weeks to about 24 weeks, from about 8 weeks toabout 20 weeks, or from about 12 weeks to about 16 weeks), or more,following the initial administration of the CYP51A1 inhibitor to thesubject, such as within 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7days, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44weeks, 45 weeks, 46 weeks, 47 weeks, 48 weeks, or more, following theinitial administration of the CYP51A1 inhibitor to the subject); (iii) areduction in decremental responses exhibited by the subject uponrepetitive nerve stimulation, such as a reduction that is observedwithin one or more days, weeks, or months following administration ofthe CYP51A1 inhibitor (e.g., a reduction that is observed within fromabout 1 day to about 48 weeks (e.g., within from about 2 days to about36 weeks, from about 4 weeks to about 24 weeks, from about 8 weeks toabout 20 weeks, or from about 12 weeks to about 16 weeks), or more,following the initial administration of the CYP51A1 inhibitor to thesubject, such as within 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7days, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44weeks, 45 weeks, 46 weeks, 47 weeks, 48 weeks, or more, following theinitial administration of the CYP51A1 inhibitor to the subject); (iv) animprovement in the subject's muscle strength, as assessed, for example,by way of the Medical Research Council muscle testing scale (asdescribed, e.g., in Jagtap et al., Ann. Indian. Acad. Neurol. 17:336-339(2014), the disclosure of which is incorporated herein by reference asit pertains to measuring patient response to neurological diseasetreatment), such as an improvement that is observed within one or moredays, weeks, or months following administration of the CYP51A1 inhibitor(e.g., an improvement that is observed within from about 1 day to about48 weeks (e.g., within from about 2 days to about 36 weeks, from about 4weeks to about 24 weeks, from about 8 weeks to about 20 weeks, or fromabout 12 weeks to about 16 weeks), or more, following the initialadministration of the CYP51A1 inhibitor to the subject, such as within 1day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 2 weeks, 3 weeks, 4weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks,12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47weeks, 48 weeks, or more, following the initial administration of theCYP51A1 inhibitor to the subject); (v) an improvement in the subject'squality of life, as assessed, for example, using the amyotrophic lateralsclerosis-specific quality of life (ALS-specific QOL) questionnaire,such as an improvement in the subject's quality of life that is observedwithin one or more days, weeks, or months following administration ofthe CYP51A1 inhibitor (e.g., an improvement in the subject's quality oflife that is observed within from about 1 day to about 48 weeks (e.g.,within from about 2 days to about 36 weeks, from about 4 weeks to about24 weeks, from about 8 weeks to about 20 weeks, or from about 12 weeksto about 16 weeks), or more, following the initial administration of theCYP51A1 inhibitor to the subject, such as within 1 day, 2 days, 3 days,4 days, 5 days, 6 days, 7 days, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48weeks, or more, following the initial administration of the CYP51A1inhibitor to the subject); (vi) a decrease in the frequency and/orseverity of muscle cramps exhibited by the subject, such as a decreasein cramp frequency and/or severity within one or more days, weeks, ormonths following administration of the CYP51A1 inhibitor (e.g., adecrease in cramp frequency and/or severity within from about 1 day toabout 48 weeks (e.g., within from about 2 days to about 36 weeks, fromabout 4 weeks to about 24 weeks, from about 8 weeks to about 20 weeks,or from about 12 weeks to about 16 weeks), or more, following theinitial administration of the CYP51A1 inhibitor to the subject, such aswithin 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 2 weeks, 3weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks,11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46weeks, 47 weeks, 48 weeks, or more, following the initial administrationof the CYP51A1 inhibitor to the subject); and (vii) a decrease in TDP-43aggregation exhibited by the patient, such as a decrease in TDP-43aggregation within one or more days, weeks, or months followingadministration of the CYP51A1 inhibitor (e.g., a decrease in TDP-43aggregation within from about 1 day to about 48 weeks (e.g., within fromabout 2 days to about 36 weeks, from about 4 weeks to about 24 weeks,from about 8 weeks to about 20 weeks, or from about 12 weeks to about 16weeks), or more, following the initial administration of the CYP51A1inhibitor to the subject, such as within 1 day, 2 days, 3 days, 4 days,5 days, 6 days, 7 days, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 weeks, ormore, following the initial administration of the CYP51A1 inhibitor tothe subject.

As used herein, the term “treatment period” refers to a duration of timeover which a patient may be administered a therapeutic agent, such as aCYP51A1 inhibitor as described herein, so as to treat or prevent aneurological disorder. Treatment periods as described herein may have aduration of several hours, days, weeks, months, or years.

As used herein, the term “alkyl” refers to monovalent, optionallybranched alkyl groups, such as those having from 1 to 6 carbon atoms, ormore. This term is exemplified by groups such as methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-hexyl and thelike.

As used herein, the term “lower alkyl” refers to alkyl groups havingfrom 1 to 6 carbon atoms.

As used herein, the term “aryl” refers to an unsaturated aromaticcarbocyclic group of from 6 to 14 carbon atoms having a single ring(e.g., phenyl) or multiple condensed rings (e.g., naphthyl). Preferredaryl include phenyl, naphthyl, phenanthrenyl and the like.

As used herein, the terms “aralkyl” and “aryl alkyl” are usedinterchangeably and refer to an alkyl group containing an aryl moiety.Similarly, the terms “aryl lower alkyl” and the like refer to loweralkyl groups containing an aryl moiety.

As used herein, the term “alkyl aryl” refers to alkyl groups having anaryl substituent, including benzyl, phenethyl and the like.

As used herein, the term “heteroaryl” refers to a monocyclicheteroaromatic, or a bicyclic or a tricyclic fused-ring heteroaromaticgroup. Particular examples of heteroaromatic groups include optionallysubstituted pyridyl, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl,isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, 1,2,3-triazolyl,1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadia-zolyl,1,2,5-oxadiazolyl, I,3,4-oxadiazolyl,I,3,4-triazinyl, 1,2,3-triazinyl,benzofuryl, [2,3-dihydrojbenzofuryl, isobenzofuryl, benzothienyl,benzotriazolyl, isobenzothienyl, indolyl, isoindolyl, 3H-indolyl,benzimidazolyl, imidazo[I,2-a]pyridyl, benzothiazolyl, benzoxa-zolyl,quinolizinyl, quinazolinyl, pthalazinyl, quinoxalinyl, cinnolinyl,napthyridinyl, pyrido[3,4-b]pyridyl, pyrido[3,2-b]pyridyl,pyrido[4,3-b]pyridyl, quinolyl, isoquinolyl, tetrazolyl,5,6,7,8-tetrahydroquinolyl, 5,6,7,8-tetrahydroisoquinolyl, purinyl,pteridinyl, carbazolyl, xanthenyl, benzoquinolyl, and the like.

As used herein, the term “alkyl heteroaryl” refers to alkyl groupshaving a heteroaryl substituent, including 2-furylmethyl,2-thienylmethyl, 2-(1H-indol-3-yl)ethyl and the like.

As used herein, the term “lower alkenyl” refers to alkenyl groupspreferably having from 2 to 6 carbon atoms and having at least 1 or 2sites of alkenyl unsaturation. Exemplary alkenyl groups are ethenyl(—CH═CH₂), n-2-propenyl (allyl, —CH₂CH═CH₂) and the like.

As used herein, the term “alkenyl aryl” refers to alkenyl groups havingan aryl substituent, including 2-phenylvinyl and the like.

As used herein, the term “alkenyl heteroaryl” refers to alkenyl groupshaving a heteroaryl substituent, including 2-(3-pyridinyl)vinyl and thelike.

As used herein, the term “lower alkynyl” refers to alkynyl groupspreferably having from 2 to 6 carbon atoms and having at least 1-2 sitesof alkynyl unsaturation, preferred alkynyl groups include ethynyl(—C≡CH), propargyl (—CH₂C≡CH), and the like.

As used herein, the term “alkynyl aryl” refers to alkynyl groups havingan aryl substituent, including phenylethynyl and the like.

As used herein, the term “alkynyl heteroaryl” refers to alkynyl groupshaving a heteroaryl substituent, including 2-thienylethynyl and thelike.

As used herein, the term “cycloalkyl” refers to a monocyclic cycloalkylgroup having from 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.

As used herein, the term “lower cycloalkyl” refers to a saturatedcarbocyclic group of from 3 to 8 carbon atoms having a single ring(e.g., cyclohexyl) or multiple condensed rings (e.g., norbornyl).Preferred cycloalkyl include cyclopentyl, cyclohexyl, norbornyl and thelike.

As used herein, the term “heterocycloalkyl” refers to a cycloalkyl groupin which one or more ring carbon atoms are replaced with a heteroatom,such as a nitrogen atom, an oxygen atom, a sulfur atom, and the like.Exemplary heterocycloalkyl groups are pyrrolidinyl, piperidinyl,oxopiperidinyl, morpholinyl, piperazinyl, oxopiperazinyl,thiomorpholinyl, azepanyl, diazepanyl, oxazepanyl, thiazepanyl,dioxothiazepanyl, azokanyl, tetrahydrofuranyl, tetrahydropyranyl, andthe like.

As used herein, the term “alkyl cycloalkyl” refers to alkyl groupshaving a cycloalkyl substituent, including cyclohexylmethyl,cyclopentylpropyl, and the like.

As used herein, the term “alkyl heterocycloalkyl” refers to C₁-C₆-alkylgroups having a heterocycloalkyl substituent, including2-(1-pyrrolidinyl)ethyl, 4-morpholinylmethyl,(1-methyl-4-piperidinyl)methyl and the like.

As used herein, the term “carboxy” refers to the group —C(O)OH.

As used herein, the term “alkyl carboxy” refers to C₁-C₅-alkyl groupshaving a carboxy substituent, including 2-carboxyethyl and the like.

As used herein, the term “acyl” refers to the group —C(O)R, wherein Rmay be, for example, C₁-C₆-alkyl, aryl, heteroaryl, C₁-C₆-alkyl aryl, orC₁-C₆-alkyl heteroaryl, among other substituents. As used herein, theterm “acyloxy” refers to the group —OC(O)R, wherein R may be, forexample, C₁-C₆-alkyl, aryl, heteroaryl, C₁-C₆-alkyl aryl, or C₁-C₆-alkylheteroaryl, among other substituents.

As used herein, the term “alkoxy” refers to the group —O—R, wherein Ris, for example, an optionally substituted alkyl group, such as anoptionally substituted C₁-C₆-alkyl, aryl, heteroaryl, C₁-C₆-alkyl aryl,or C₁-C₆-alkyl heteroaryl, among other substituents. Exemplary alkoxygroups include by way of example, methoxy, ethoxy, phenoxy, and thelike.

As used herein, the term “alkoxycarbonyl” refers to the group —C(O)OR,wherein R is, for example, hydrogen, C₁-C₆-alkyl, aryl, heteroaryl,C₁-C₆-alkyl aryl, or C₁-C₆-alkyl heteroaryl, among other possiblesubstituents.

As used herein, the term “alkyl alkoxycarbonyl” refers to alkyl groupshaving an alkoxycarbonyl substituent, including2-(benzyloxycarbonyl)ethyl and the like.

As used herein, the term “aminocarbonyl” refers to the group —C(O)NRR′,wherein each of R and R′ may independently be, for example, hydrogen,C₁-C₆-alkyl, aryl, heteroaryl, C₁-C₆-alkyl aryl, or C₁-C₆-alkylheteroaryl, among other substituents.

As used herein, the term “alkyl aminocarbonyl” refers to alkyl groupshaving an aminocarbonyl substituent, including2-(dimethylaminocarbonyl)ethyl and the like.

As used herein, the term “acylamino” refers to the group —NRC(O)R′,wherein each of R and R′ may independently be, for example, hydrogen,C₁-C₆-alkyl, aryl, heteroaryl, C₁-C₆-alkyl aryl, or C₁-C₆-alkylheteroaryl, among other substituents.

As used herein, the term “alkyl acylamino” refers to alkyl groups havingan acylamino substituent, including 2-(propionylamino)ethyl and thelike.

As used herein, the term “ureido” refers to the group —NRC(O)NR′R″,wherein each of R, R′, and R″ may independently be, for example,hydrogen, C₁-C₆-alkyl, aryl, heteroaryl, C₁-C₆-alkyl aryl, C₁-C₆-alkylheteroaryl, cycloalkyl, or heterocycloalkyl, among other substituents.Exemplary ureido groups further include moieties in which R′ and R″,together with the nitrogen atom to which they are attached, form a3-8-membered heterocycloalkyl ring.

As used herein, the term “alkyl ureido” refers to alkyl groups having anureido substituent, including 2-(N′-methylureido)ethyl and the like.

As used herein, the term “amino” refers to the group —NRR′, wherein eachof R and R′ may independently be, for example, hydrogen, C₁-C₆-alkyl,aryl, heteroaryl, C₁-C₆-alkyl aryl, C₁-C₆-alkyl heteroaryl, cycloalkyl,or heterocycloalkyl, among other substituents. Exemplary amino groupsfurther include moieties in which R and R′, together with the nitrogenatom to which they are attached, can form a 3-8-memberedheterocycloalkyl ring.

As used herein, the term “alkyl amino” refers to alkyl groups having anamino substituent, including 2-(1-pyrrolidinyl)ethyl and the like.

As used herein, the term “ammonium” refers to a positively charged group—N+RR′R″, wherein each of R, R′, and R″ may independently be, forexample, C₁-C₆-alkyl, C₁-C₆-alkyl aryl, C₁-C₆-alkyl heteroaryl,cycloalkyl, or heterocycloalkyl, among other substituents. Exemplaryammonium groups further include moieties in which R and R′, togetherwith the nitrogen atom to which they are attached, form a 3-8-memberedheterocycloalkyl ring.

As used herein, the term “halogen” refers to fluoro, chloro, bromo andiodo atoms.

As used herein, the term “sulfonyloxy” refers to a group —OSO₂—R whereinR is selected from hydrogen, C₁-C₆-alkyl, C₁-C₆-alkyl substituted withhalogens, e.g., an —OSO₂—CF₃ group, aryl, heteroaryl, C₁-C₆-alkyl aryl,and C₁-C₆-alkyl heteroaryl.

As used herein, the term “alkyl sulfonyloxy” refers to alkyl groupshaving a sulfonyloxy substituent, including 2-(methylsulfonyloxy)ethyland the like.

As used herein, the term “sulfonyl” refers to group “—SO₂—R” wherein Ris selected from hydrogen, aryl, heteroaryl, C₁-C₆-alkyl, C₁-C₆-alkylsubstituted with halogens, e.g., an —SO₂—CF₃ group, C₁-C₆-alkyl aryl orC₁-C₆-alkyl heteroaryl.

As used herein, the term “alkyl sulfonyl” refers to alkyl groups havinga sulfonyl substituent, including 2-(methylsulfonyl)ethyl and the like.

As used herein, the term “sulfinyl” refers to a group “—S(O)—R” whereinR is selected from hydrogen, C₁-C₆-alkyl, C₁-C₆-alkyl substituted withhalogens, e.g., a —SO—CF₃ group, aryl, heteroaryl, C₁-C₆-alkyl aryl orC₁-C₆-alkyl heteroaryl.

As used herein, the term “alkyl sulfinyl” refers to C₁-C₅-alkyl groupshaving a sulfinyl substituent, including 2-(methylsulfinyl)ethyl and thelike.

As used herein, the term “sulfanyl” refers to groups —S—R, wherein R is,for example, alkyl, aryl, heteroaryl, C₁-C₆-alkyl aryl, or C₁-C₆-alkylheteroaryl, among other substituents. Exemplary sulfanyl groups aremethylsulfanyl, ethylsulfanyl, and the like.

As used herein, the term “alkyl sulfanyl” refers to alkyl groups havinga sulfanyl substituent, including 2-(ethylsulfanyl)ethyl and the like.

As used herein, the term “sulfonylamino” refers to a group —NRSO₂—R′,wherein each of R and R′ may independently be hydrogen, C₁-C₆-alkyl,aryl, heteroaryl, C₁-C₆-alkyl aryl, or C₁-C₆-alkyl heteroaryl, amongother substituents.

As used herein, the term “alkyl sulfonylamino” refers to alkyl groupshaving a sulfonylamino substituent, including2-(ethylsulfonylamino)ethyl and the like.

Unless otherwise constrained by the definition of the individualsubstituent, the above set out groups, like “alkyl”, “alkenyl”,“alkynyl”, “aryl” and “heteroaryl” etc. groups can optionally besubstituted, for example, with one or more substituents, as valencypermits, such as a substituent selected from alkyl (e.g., C₁-C₆-alkyl),alkenyl (e.g., C₂-C₆-alkenyl), alkynyl (e.g., C₂-C₆-alkynyl),cycloalkyl, heterocycloalkyl, alkyl aryl (e.g., C₁-C₆-alkyl aryl), alkylheteroaryl (e.g., C₁-C₆-alkyl heteroaryl, alkyl cycloalkyl (e.g.,C₁-C₆-alkyl cycloalkyl), alkyl heterocyloalyl (e.g., C₁-C₆-alkylheterocycloalkyl), amino, ammonium, acyl, acyloxy, acylamino,aminocarbonyl, alkoxycarbonyl, ureido, aryl, heteroaryl, sulfinyl,sulfonyl, alkoxy, sulfanyl, halogen, carboxy, trihalomethyl, cyano,hydroxy, mercapto, nitro, and the like. In some embodiments, thesubstitution is one in which neighboring substituents have undergonering closure, such as situations in which vicinal functionalsubstituents are involved, thus forming, e.g., lactams, lactones, cyclicanhydrides, acetals, thioacetals, and aminals, among others.

As used herein, the term “optionally fused” refers to a cyclic chemicalgroup that may be fused with a ring system, such as cycloalkyl,heterocycloalkyl, aryl, or heteroaryl. Exemplary ring systems that maybe fused to an optionally fused chemical group include, e.g., indolyl,isoindolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl,benzoxazolyl, benzothiazolyl, benzoisoxazolyl, benzoisothiazolyl,indazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, phthalazinyl,quinoxalinyl, quinazolinyl, cinnolinyl, indolizinyl, naphthyridinyl,pteridinyl, indanyl, naphtyl, 1,2,3,4-tetrahydronaphthyl, indolinyl,isoindolinyl, 2,3,4,5-tetrahydrobenzo[b]oxepinyl,6,7,8,9-tetrahydro-5H-benzocycloheptenyl, chromanyl, and the like.

As used herein, the term “pharmaceutically acceptable salt” refers to asalt, such as a salt of a compound described herein, that retains thedesired biological activity of the non-ionized parent compound fromwhich the salt is formed. Examples of such salts include, but are notrestricted to acid addition salts formed with inorganic acids (e.g.,hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid,nitric acid, and the like), and salts formed with organic acids such asacetic acid, oxalic acid, tartaric acid, succinic acid, malic acid,fumaric acid, maleic acid, ascorbic acid, benzoic acid, tannic acid,pamoic acid, alginic acid, polyglutamic acid, naphthalene sulfonic acid,naphthalene disulfonic acid, and poly-galacturonic acid. The compoundscan also be administered as pharmaceutically acceptable quaternarysalts, such as quaternary ammonium salts of the formula —NR,R′,R″+Z⁻,wherein each of R, R′, and R″ may independently be, for example,hydrogen, alkyl, benzyl, C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl,C₁-C₆-alkyl aryl, C₁-C₆-alkyl heteroaryl, cycloalkyl, heterocycloalkyl,or the like, and Z is a counterion, such as chloride, bromide, iodide,—O-alkyl, toluenesulfonate, methyl sulfonate, sulfonate, phosphate,carboxylate (such as benzoate, succinate, acetate, glycolate, maleate,malate, fumarate, citrate, tartrate, ascorbate, cinnamoate, mandeloate,and diphenylacetate), or the like.

As used herein in the context of a CYP51A1 inhibitor, the term “variant”refers to an agent containing one or more modifications relative to areference agent and that (i) retains an ability to inhibit CYP51A1and/or (ii) is converted in vivo into an agent that inhibits CYP51A1. Inthe context of small molecule CYP51A1 inhibitors, structural variants ofa reference compound include those that differ from the referencecompound by the inclusion and/or location of one or more substituents,as well as variants that are isomers of a reference compound, such asstructural isomers (e.g., regioisomers) or stereoisomers (e.g.,enantiomers or diastereomers), as well as prodrugs of a referencecompound. In the context of an antibody or antigen-binding fragmentthereof, a variant may contain one or more amino acid substitutions,such as one or more conservative amino acid substitutions, relative tothe parent antibody or antigen-binding fragment thereof. In the contextof an interfering RNA molecule, a variant may contain one or morenucleic acid substitutions relative to a parent interfering RNAmolecule.

The structural compositions described herein also include the tautomers,geometrical isomers (e.g., E/Z isomers and cis/trans isomers),enantiomers, diastereomers, and racemic forms, as well aspharmaceutically acceptable salts thereof. Such salts include, e.g.,acid addition salts formed with pharmaceutically acceptable acids likehydrochloride, hydrobromide, sulfate or bisulfate, phosphate or hydrogenphosphate, acetate, benzoate, succinate, fumarate, maleate, lactate,citrate, tartrate, gluconate, methanesulfonate, benzenesulfonate, andpara-toluenesulfonate salts.

As used herein, chemical structural formulas that do not depict thestereochemical configuration of a compound having one or morestereocenters will be interpreted as encompassing any one of thestereoisomers of the indicated compound, or a mixture of one or moresuch stereoisomers (e.g., any one of the enantiomers or diastereomers ofthe indicated compound, or a mixture of the enantiomers (e.g., a racemicmixture) or a mixture of the diastereomers). As used herein, chemicalstructural formulas that do specifically depict the stereochemicalconfiguration of a compound having one or more stereocenters will beinterpreted as referring to the substantially pure form of theparticular stereoisomer shown.

“Substantially pure” forms refer to compounds having a purity of greaterthan 85%, such as a purity of from 85% to 99%, 85% to 99.9%, 85% to99.99%, or 85% to 100%, such as a purity of 85%, 86%, 87%, 88%, 89%,90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9%, 99.99%,99.999%, or 100%, as assessed, for example, using chromatography andnuclear magnetic resonance techniques known in the art.

As used herein, the term “antibody” (Ab) refers to an immunoglobulinmolecule that specifically binds to, or is immunologically reactivewith, a particular antigen, and includes polyclonal, monoclonal,genetically engineered, and otherwise modified forms of antibodies,including, but not limited to, chimeric antibodies, humanizedantibodies, heteroconjugate antibodies (e.g., bi- tri- and quad-specificantibodies, diabodies, triabodies, and tetrabodies), and antigen-bindingfragments of antibodies, including e.g., Fab′, F(ab′)₂, Fab, Fv, rlgG,and scFv fragments. In some embodiments, two or more portions of animmunoglobulin molecule are covalently bound to one another, e.g., viaan amide bond, a thioether bond, a carbon-carbon bond, a disulfidebridge, or by a linker, such as a linker described herein or known inthe art. Antibodies also include antibody-like protein scaffolds, suchas the tenth fibronectin type III domain (¹⁰Fn3), which contains BC, DE,and FG structural loops similar in structure and solvent accessibilityto antibody complementarity-determining regions (CDRs). The tertiarystructure of the ¹⁰Fn3 domain resembles that of the variable region ofthe IgG heavy chain, and one of skill in the art can graft, e.g., theCDRs of a reference antibody onto the fibronectin scaffold by replacingresidues of the BC, DE, and FG loops of ¹⁰Fn3 with residues from theCDR-H1, CDR-H2, or CDR-H3 regions, respectively, of the referenceantibody.

The term “antigen-binding fragment,” as used herein, refers to one ormore fragments of an antibody that retain the ability to specificallybind to a target antigen. The antigen-binding function of an antibodycan be performed by fragments of a full-length antibody. The antibodyfragments can be a Fab, F(ab′)₂, scFv, SMIP, diabody, a triabody, anaffibody, a nanobody, an aptamer, or a domain antibody. Examples ofbinding fragments encompassed of the term “antigen-binding fragment” ofan antibody include, but are not limited to: (i) a Fab fragment, amonovalent fragment consisting of the V_(L), V_(H), C_(L), and C_(H)1domains; (ii) a F(ab′)2 fragment, a bivalent fragment comprising two Fabfragments linked by a disulfide bridge at the hinge region; (iii) a Fdfragment consisting of the V_(H) and C_(H)1 domains; (iv) a Fv fragmentconsisting of the V_(L) and V_(H) domains of a single arm of anantibody, (v) a dAb including V_(H) and V_(L) domains; (vi) a dAbfragment (Ward et al., Nature 341:544-546, 1989), which consists of aV_(H) domain; (vii) a dAb which consists of a V_(H) or a V_(L) domain;(viii) an isolated CDR; and (ix) a combination of two or more isolatedCDRs which may optionally be joined by a synthetic linker. Furthermore,although the two domains of the Fv fragment, V_(L) and V_(H), are codedfor by separate genes, they can be joined, using recombinant methods, bya linker that enables them to be made as a single protein chain in whichthe V_(L) and V_(H) regions pair to form monovalent molecules (known assingle-chain Fv (scFv); see, e.g., Bird et al., Science 242:423-426,1988, and Huston et al., Proc. Natl. Acad. Sci. USA 85:5879-5883, 1988).These antibody fragments can be obtained using conventional techniquesknown to those of skill in the art, and the fragments can be screenedfor utility in the same manner as intact antibodies. Antigen-bindingfragments can be produced by recombinant DNA techniques, enzymatic orchemical cleavage of intact immunoglobulins, or, in some embodiments, bychemical peptide synthesis procedures known in the art.

As used herein, the term “bispecific antibodies” refers to monoclonal,often human or humanized antibodies that have binding specificities forat least two different antigens.

As used herein, the term “chimeric” antibody refers to an antibodyhaving variable domain sequences (e.g., CDR sequences) derived from animmunoglobulin of one source organism, such as rat or mouse, andconstant regions derived from an immunoglobulin of a different organism(e.g., a human, another primate, pig, goat, rabbit, hamster, cat, dog,guinea pig, member of the bovidae family (such as cattle, bison,buffalo, elk, and yaks, among others), cow, sheep, horse, or bison,among others). Methods for producing chimeric antibodies are known inthe art. See, e.g., Morrison, 1985, Science 229(4719): 1202-7; Oi et al,1986, BioTechniques 4:214-221; Gillies et al, 1985, J. Immunol. Methods125:191-202; U.S. Pat. Nos. 5,807,715; 4,816,567; and 4,816,397;incorporated herein by reference.

As used herein, the term “complementarity-determining region” (CDR)refers to a hypervariable region found both in the light chain and theheavy chain variable domains. The more highly conserved portions ofvariable domains are called the framework regions (FRs). As isappreciated in the art, the amino acid positions that delineate ahypervariable region of an antibody can vary, depending on the contextand the various definitions known in the art. Some positions within avariable domain may be viewed as hybrid hypervariable positions in thatthese positions can be deemed to be within a hypervariable region underone set of criteria while being deemed to be outside a hypervariableregion under a different set of criteria. One or more of these positionscan also be found in extended hypervariable regions. The antibodiesdescribed herein may comprising modifications in these hybridhypervariable positions. The variable domains of native heavy and lightchains each comprise four framework regions that primarily adopt aβ-sheet configuration, connected by three CDRs, which form loops thatconnect, and in some cases form part of, the β-sheet structure. The CDRsin each chain are held together in close proximity by the FR regions inthe order FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4 and, with the CDRs from theother antibody chains, contribute to the formation of the target bindingsite of antibodies (see Kabat et al, Sequences of Proteins ofImmunological Interest (National Institute of Health, Bethesda, Md.1987; incorporated herein by reference). As used herein, numbering ofimmunoglobulin amino acid residues is done according to theimmunoglobulin amino acid residue numbering system of Kabat et al,unless otherwise indicated.

As used herein, the term “derivatized antibodies” refers to antibodiesthat are modified by a chemical reaction so as to cleave residues or addchemical moieties not native to an isolated antibody. Derivatizedantibodies can be obtained by glycosylation, acetylation, pegylation,phosphorylation, amidation, derivatization by addition of known chemicalprotecting/blocking groups, proteolytic cleavage, linkage to a cellularligand or other protein. Any of a variety of chemical modifications canbe carried out by known techniques, including, without limitation,specific chemical cleavage, acetylation, formylation, metabolicsynthesis of tunicamycin, etc. using established procedures.Additionally, the derivative can contain one or more non-natural aminoacids, e.g., using amber suppression technology (see, e.g., U.S. Pat.No. 6,964,859; incorporated herein by reference).

As used herein, the term “diabodies” refers to bivalent antibodiescomprising two polypeptide chains, in which each polypeptide chainincludes V_(H) and V_(L) domains joined by a linker that is too short(e.g., a linker composed of five amino acids) to allow forintramolecular association of VH and VL domains on the same peptidechain. This configuration forces each domain to pair with acomplementary domain on another polypeptide chain so as to form ahomodimeric structure. Accordingly, the term “triabodies” refers totrivalent antibodies comprising three peptide chains, each of whichcontains one VH domain and one VL domain joined by a linker that isexceedingly short (e.g., a linker composed of 1-2 amino acids) to permitintramolecular association of VH and VL domains within the same peptidechain. In order to fold into their native structure, peptides configuredin this way typically trimerize so as to position the VH and VL domainsof neighboring peptide chains spatially proximal to one another topermit proper folding (see Holliger et al., Proc. Natl. Acad. Sci. USA90:6444-48, 1993; incorporated herein by reference).

As used herein, the term “framework region” or “FW region” includesamino acid residues that are adjacent to the CDRs. FW region residuesmay be present in, for example, human antibodies, rodent-derivedantibodies (e.g., murine antibodies), humanized antibodies, primatizedantibodies, chimeric antibodies, antibody fragments (e.g., Fabfragments), single-chain antibody fragments (e.g., scFv fragments),antibody domains, and bispecific antibodies, among others.

As used herein, the term “heterospecific antibodies” refers tomonoclonal, preferably human or humanized, antibodies that have bindingspecificities for at least two different antigens. Traditionally, therecombinant production of heterospecific antibodies is based on theco-expression of two immunoglobulin heavy chain-light chain pairs, wherethe two heavy chains have different specificities (Milstein et al.,Nature 305:537, 1983). Similar procedures are disclosed, e.g., in WO93/08829, U.S. Pat. Nos. 6,210,668; 6,193,967; 6,132,992; 6,106,833;6,060,285; 6,037,453; 6,010,902; 5,989,530; 5,959,084; 5,959,083;5,932,448; 5,833,985; 5,821,333; 5,807,706; 5,643,759, 5,601,819;5,582,996, 5,496,549, 4,676,980, WO 91/00360, WO 92/00373, EP 03089,Traunecker et al., EMBO J. 10:3655 (1991), Suresh et al., Methods inEnzymology 121:210 (1986); incorporated herein by reference.Heterospecific antibodies can include Fc mutations that enforce correctchain association in multi-specific antibodies, as described by Klein etal, mAbs 4(6):653-663, 2012; incorporated herein by reference.

As used herein, the term “human antibody” refers to an antibody in whichsubstantially every part of the protein (e.g., CDR, framework, C_(L),C_(H) domains (e.g., C_(H)1, C_(H)2, C_(H)3), hinge, (V_(L), V_(H))) issubstantially non-immunogenic in humans, with only minor sequencechanges or variations. A human antibody can be produced in a human cell(e.g., by recombinant expression), or by a non-human animal or aprokaryotic or eukaryotic cell that is capable of expressingfunctionally rearranged human immunoglobulin (e.g., heavy chain and/orlight chain) genes. Further, when a human antibody is a single-chainantibody, it can include a linker peptide that is not found in nativehuman antibodies. For example, an Fv can comprise a linker peptide, suchas two to about eight glycine or other amino acid residues, whichconnects the variable region of the heavy chain and the variable regionof the light chain. Such linker peptides are considered to be of humanorigin. Human antibodies can be made by a variety of methods known inthe art including phage display methods using antibody libraries derivedfrom human immunoglobulin sequences. See U.S. Pat. Nos. 4,444,887 and4,716,111; and PCT publications WO 1998/46645; WO 1998/50433; WO1998/24893; WO 1998/16654; WO 1996/34096; WO 1996/33735; and WO1991/10741; incorporated herein by reference. Human antibodies can alsobe produced using transgenic mice that are incapable of expressingfunctional endogenous immunoglobulins, but which can express humanimmunoglobulin genes. See, e.g., PCT publications WO 98/24893; WO92/01047; WO 96/34096; WO 96/33735; U.S. Pat. Nos. 5,413,923; 5,625,126;5,633,425; 5,569,825; 5,661,016; 5,545,806; 5,814,318; 5,885,793;5,916,771; and 5,939,598; incorporated by reference herein.

As used herein, the term “humanized” antibodies refers to forms ofnon-human (e.g., murine) antibodies that are chimeric immunoglobulins,immunoglobulin chains or fragments thereof (such as Fv, Fab, Fab′,F(ab′)₂ or other target-binding subdomains of antibodies) which containminimal sequences derived from non-human immunoglobulin. In general, thehumanized antibody will comprise substantially all of at least one, andtypically two, variable domains, in which all or substantially all ofthe CDR regions correspond to those of a non-human immunoglobulin. Allor substantially all of the FR regions may also be those of a humanimmunoglobulin sequence. The humanized antibody can also comprise atleast a portion of an immunoglobulin constant region (Fc), typicallythat of a human immunoglobulin consensus sequence. Methods of antibodyhumanization are known in the art. See, e.g., Riechmann et al., Nature332:323-7, 1988; U.S. Pat. Nos. 5,530,101; 5,585,089; 5,693,761;5,693,762; and U.S. Pat. No. 6,180,370 to Queen et al; EP239400; PCTpublication WO 91/09967; U.S. Pat. No. 5,225,539; EP592106; andEP519596; incorporated herein by reference.

As used herein, the term “monoclonal antibody” refers to an antibodythat is derived from a single clone, including any eukaryotic,prokaryotic, or phage clone, and not the method by which it is produced.

As used herein, the term “multi-specific antibodies” refers toantibodies that exhibit affinity for more than one target antigen.Multi-specific antibodies can have structures similar to fullimmunoglobulin molecules and include Fc regions, for example IgG Fcregions. Such structures can include, but not limited to, IgG-Fv,IgG-(scFv)₂, DVD-Ig, (scFv)₂-(scFv)₂-Fc and (scFv)₂-Fc-(scFv)₂. In caseof IgG-(scFv)₂, the scFv can be attached to either the N-terminal or theC-terminal end of either the heavy chain or the light chain. Exemplarymulti-specific molecules have been reviewed by Kontermann, 2012, mAbs4(2):182-197, Yazaki et al, 2013, Protein Engineering, Design &Selection 26(3):187-193, and Grote et al, 2012, in Proetzel & Ebersbach(eds.), Antibody Methods and Protocols, Methods in Molecular Biologyvol. 901, chapter 16:247-263; incorporated herein by reference. In someembodiments, antibody fragments can be components of multi-specificmolecules without Fc regions, based on fragments of IgG or DVD or scFv.Exemplary multi-specific molecules that lack Fc regions and into whichantibodies or antibody fragments can be incorporated include scFv dimers(diabodies), trimers (triabodies) and tetramers (tetrabodies), Fabdimers (conjugates by adhesive polypeptide or protein domains) and Fabtrimers (chemically conjugated), are described by Hudson and Souriau,2003, Nature Medicine 9:129-134; incorporated herein by reference.

As used herein, the term “primatized antibody” refers to an antibodycomprising framework regions from primate-derived antibodies and otherregions, such as CDRs and/or constant regions, from antibodies of anon-primate source. Methods for producing primatized antibodies areknown in the art. See e.g., U.S. Pat. Nos. 5,658,570; 5,681,722; and5,693,780; incorporated herein by reference. For instance, a primatizedantibody or antigen-binding fragment thereof described herein can beproduced by inserting the CDRs of a non-primate antibody orantigen-binding fragment thereof into an antibody or antigen-bindingfragment thereof that contains one or more framework regions of aprimate.

As used herein, the term “scFv” refers to a single-chain Fv antibody inwhich the variable domains of the heavy chain and the light chain froman antibody have been joined to form one chain. scFv fragments contain asingle polypeptide chain that includes the variable region of anantibody light chain (VL) (e.g., CDR-L1, CDR-L2, and/or CDR-L3) and thevariable region of an antibody heavy chain (VH) (e.g., CDR-H1, CDR-H2,and/or CDR-H3) separated by a linker. The linker that joins the VL andVH regions of a scFv fragment can be a peptide linker composed ofproteinogenic amino acids. Alternative linkers can be used to so as toincrease the resistance of the scFv fragment to proteolytic degradation(e.g., linkers containing D-amino acids), in order to enhance thesolubility of the scFv fragment (e.g., hydrophilic linkers such aspolyethylene glycol-containing linkers or polypeptides containingrepeating glycine and serine residues), to improve the biophysicalstability of the molecule (e.g., a linker containing cysteine residuesthat form intramolecular or intermolecular disulfide bonds), or toattenuate the immunogenicity of the scFv fragment (e.g., linkerscontaining glycosylation sites). scFv molecules are known in the art andare described, e.g., in U.S. Pat. No. 5,892,019, Flo et al., (Gene77:51, 1989); Bird et al., (Science 242:423, 1988); Pantoliano et al.,(Biochemistry 30:10117, 1991); Milenic et al., (Cancer Research 51:6363,1991); and Takkinen et al., (Protein Engineering 4:837, 1991). The VLand VH domains of a scFv molecule can be derived from one or moreantibody molecules. It will also be understood by one of ordinary skillin the art that the variable regions of the scFv molecules describedherein can be modified such that they vary in amino acid sequence fromthe antibody molecule from which they were derived. For example, in oneembodiment, nucleotide or amino acid substitutions leading toconservative substitutions or changes at amino acid residues can be made(e.g., in CDR and/or framework residues). Alternatively or in addition,mutations are made to CDR amino acid residues to optimize antigenbinding using art recognized techniques. scFv fragments are described,for example, in WO 2011/084714; incorporated herein by reference.

BRIEF DESCRIPTION OF THE FIGURES

FIGS. 1A-1C demonstrate that the viability of a yeast TDP-43 model isrestored by the Erg11 inhibitor, fluconazole. (FIG. 1A) Structure of theErg11 inhibitor and anti-fungal, fluconazole. (FIG. 1B) Fluconazolerescues viability of TDP-43-expressing yeast using a resazurin-reductionendpoint. A 2-fold serial dilution of fluconazole was applied toTDP-43-expressing yeast for 24 hours prior to analysis. (FIG. 1C)Wild-type yeast cultures were treated with fluconazole for eight hoursprior to HPLC analysis for lanosterol and ergosterol. Data are expressedas the area under the curve (AUC) normalized to cell mass based onoptical density of cultures at 600 nm. Fluconazole treatment reducesergosterol, while simultaneously leading to an increase in the Erg11substrate, lanosterol.

FIG. 2 shows the structures of compounds used in primary rat corticalneuron TDP-43 wild type and Q331K mutant survival studies.

FIGS. 3A and 3B demonstrate that compound (3) promotes survival inprimary rat cortical neurons transfected with wild-type TDP-43. Ratprimary cortical neurons were co-transfected with a red fluorescentprotein (RFP) as a morphological marker and either control (emptyvector) or wild-type TDP-43 expression plasmids and treated with vehicle(DMSO) or a titration of compound (3). (FIG. 3A) Risk of neuron deathplots. The lifetime of each neuron was determined by either loss of RFPsignal or morphological indicators of death such as loss of neurites andcell blebbing and used to generate cumulative hazard plots of risk ofdeath over time (hrs) post-transfection. (FIG. 3B) Forest plots. Hazardratios for each treatment group (relative to TDP-43 DMSO group) weredetermined by cox regression analysis and used to generate forest plots.Hazard ratios (HR)<1 in which the confidence interval (CI) does notencompass 1 represent treatments that significantly reduce probabilityof neuron death relative to the TDP-43 DMSO control. P, p-value.

FIGS. 4A and 4B demonstrate that compound (3) promotes survival inprimary rat cortical neurons transfected with Q331K Mutant TDP-43. Ratprimary cortical neurons were co-transfected with a red fluorescentprotein (RFP) as a morphological marker and either control (emptyvector) or Q331K mutant TDP-43 expression plasmids and treated withvehicle (DMSO) or a titration of compound (3). (FIG. 4A) Risk of neurondeath plots. The lifetime of each neuron was determined by either lossof RFP signal or morphological indicators of death such as loss ofneurites and cell blebbing and used to generate cumulative hazard plotsof risk of death over time (hrs) post-transfection. (FIG. 4B) Forestplots. Hazard ratios for each treatment group (relative to TDP-43 DMSOgroup) were determined by cox regression analysis and used to generateforest plots. Hazard ratios (HR)<1 in which the confidence interval (CI)does not encompass 1 represent treatments that significantly reduceprobability of neuron death relative to the TDP-43 DMSO control. P,p-value.

FIGS. 5A and 5B demonstrate that compound (4) promotes survival inprimary rat cortical neurons transfected with wild-type TDP-43. Ratprimary cortical neurons were co-transfected with a red fluorescentprotein (RFP) as a morphological marker and either control (emptyvector) or wild type TDP-43 expression plasmids and treated with vehicle(DMSO) or a titration of compound (4). (FIG. 5A) Risk of neuron deathplots. The lifetime of each neuron was determined by either loss of RFPsignal or morphological indicators of death such as loss of neurites andcell blebbing and used to generate cumulative hazard plots of risk ofdeath over time (hrs) post-transfection. (FIG. 5B) Forest plots. Hazardratios for each treatment group (relative to TDP-43 DMSO group) weredetermined by cox regression analysis and used to generate forest plots.Hazard ratios (HR)<1 in which the confidence interval (CI) does notencompass 1 represent treatments that significantly reduce probabilityof neuron death relative to the TDP-43 DMSO control. P, p-value.

DETAILED DESCRIPTION

The present invention features compositions and methods for treatingneurological disorders, such as amyotrophic lateral sclerosis and otherneuromuscular disorders, as well as frontotemporal degeneration,Alzheimer's disease, Parkinson's disease, dementia with Lewy Bodies,corticobasal degeneration, progressive supranuclear palsy, dementiaparkinsonism ALS complex of Guam, Huntington's disease, Inclusion bodymyopathy with early-onset Paget disease and frontotemporal dementia(IBMPFD), sporadic inclusion body myositis, myofibrillar myopathy,dementia pugilistica, chronic traumatic encephalopathy, Alexanderdisease, and hereditary inclusion body myopathyamong others.Particularly, the invention provides inhibitors of cytochrome P450isoform 51A1 (CYP51A1), also referred to herein as lanosterol 14-alphademethylase, that may be administered to a patient (e.g., a humanpatient) so as to treat or prevent a neurological disorder, such as oneor more of the foregoing conditions. In the context of therapeutictreatment, the CYP51A1 inhibitor may be administered to the patient toalleviate one or more symptoms of the disorder and/or to remedy anunderlying molecular pathology associated with the disease, such as tosuppress or prevent aggregation of TAR-DNA binding protein (TDP)-43.

The disclosure herein is based, in part, on the discovery that CYP51A1inhibition modulates TDP-43 aggregation in vivo. Suppression of TDP-43aggregation exerts beneficial effects in patients suffering from aneurological disorder. Many pathological conditions have been correlatedwith TDP-43-promoted aggregation and toxicity, such as amyotrophiclateral sclerosis, frontotemporal degeneration, Alzheimer's disease,Parkinson's disease, dementia with Lewy Bodies, corticobasaldegeneration, progressive supranuclear palsy, dementia parkinsonism ALScomplex of Guam, Huntington's disease, IBMPFD, sporadic inclusion bodymyositis, myofibrillar myopathy, dementia pugilistica, chronic traumaticencephalopathy, Alexander disease, and hereditary inclusion bodymyopathy. Without being limited by mechanism, by administering aninhibitor of CYP51A1, patients suffering from diseases associated withTDP-43 aggregation and toxicity may be treated, for example, due to thesuppression of TDP-43 aggregation induced by the CYP51A1 inhibitor.

Patients that are likely to respond to CYP51A1 inhibition as describedherein include those that have or are at risk of developing TDP-43aggregation, such as those that express a mutant form of TDP-43associated with TDP-43 aggregation and toxicity in vivo. Examples ofsuch mutations in TDP-43 that have been correlated with elevated TDP-43aggregation and toxicity include Q331K, M337V, Q343R, N345K, R361 S, andN390D, among others. The compositions and methods described herein thusprovide the additional clinical benefit of enabling the identificationof patients that are likely to respond to CYP51A1 inhibitor therapy, aswell as processes for treating these patients accordingly.

As described in further detail below, CYP51A1 inhibitors useful inconjunction with the compositions and methods of the invention includeinhibitory small molecules, such as LEK-935, CP-320626, itraconazole,posaconazole, cyproconazole, voriconazole, fluconazole, clotrimazol,fenticonazole, epoxiconazole, ketoconazole, ravuconazole, isavuconazole,holothurin A, theasaponin, capsicosine, betulafolientriol, prochloraz,propiconazole, prothioconazole, prothioconazole-desthio, tebuconazole,triadimenol, azalanstat, and variants thereof. In some embodiments, theCYP51A1 inhibitor is an anti-CYP51A1 antibody or antigen-bindingfragment thereof, or a compound, such as an interfering RNA molecule,that attenuates CYP51A1 expression.

The sections that follow provide a description of exemplary CYP51A1inhibitors that may be used in conjunction with the compositions andmethods disclosed herein. The sections below additionally provide adescription of various exemplary routes of administration andpharmaceutical compositions that may be used for delivery of thesesubstances for the treatment of a neurological disorder.

Small Molecule CYP51A1 Inhibitors

LEK-935 and Variants Thereof

CYP51A1 inhibitors that may be used in conjunction with the compositionsand methods described herein include small molecule antagonists ofCYP51A1 activity. The CYP51A1 inhibitor may be, for example, LEK-935,represented by formula (3), herein.

In some embodiments, the CYP51A1 inhibitor is a variant of LEK-835 thatretains CYP51A1 inhibitory activity. For example, CYP51A1 inhibitorsuseful in conjunction with the compositions and methods described hereininclude those represented by formula (I)

wherein n is 1 or 2;

X is hydrogen, lower alkyl, lower alkoxy-lower alkyl, or a group X^(a)of the formula:

Z is a group of the formula:

Y is a group of the formula:

R_(O) is lower alkyl, COR₄ or C(R₅)=CHCOR₄;

R is R_(o) or is OR″;

R″ is hydrogen, lower-alkyl, lower alkanoyl, (CH₂)₁₋₆—OH,(CH₂)₁₋₆—O(CH₂)₁₋₆R₆, or (CH₂)₁₋₆—COR₄;

R₁ and R_(a) are hydrogen, lower alkanoyl, benzoyl or (CH₂)₁₋₆—OH;

R₂ and R_(b) are hydrogen, Cl, Br or CF₃;

R₃ and R₅ are hydrogen or CH₃;

R₄ is hydroxy, lower-alkoxy or N(R₇, R₈);

R₆ is hydrogen, R_(g), OH or COR₄;

R₇ and R₈ are hydrogen or lower alkyl;

R_(c) and R_(e) are hydrogen, Cl, F, Br or CF₃;

R_(d) is hydrogen or NH₂;

R_(f) is hydrogen, CH₃CONH—, NH₂COCH₂— or R₉CH₂CH₂OCH₂CH₂O—;

R_(g) and R₉ are phenyl or phenyl substituted by Cl, F or Br;

or a pharmaceutically acceptable salt, ester, or ether thereof.

In some embodiments of formula (I), n is 1, R₁ is hydrogen, R₂ ischlorine in the 6-position of a 2-pyridyl residue and Y is phenylsubstituted in the p-position by R.

In some embodiments of formula (I), X is X^(a); R^(a) is hydrogen; Z is6-chloro-2-pyridyl, and Y is phenyl substituted in the p-position by2-ethoxyethoxy, 2-phenethoxyethoxy or methoxycarbonylmethoxy.

In some embodiments of formula (I), the compound is methylα,α′-[[[(R)-p-(2-ethoxyethoxy)-α-methylphen-ethyl]imino]dimethylene]bis[(RS)-6-chloro-2-pyridinemethanol];(RS)-6-chloro-α-[[[(R)-p-(2-ethoxyethoxy)-α-methyl-phenethyl]amino]methyl]-2-pyridinemethanol;α,α′-[[[p-(2-ethoxyethoxy)phenethyl]imino]dimethylene]bis[(RS)-6-chloro-2-pyridinemethanol];(R)-6-bromo-α-[[[(RS)-2-(6-bromo-2-pyridyl)-2-hydroxyethyl][(R)-p-(2-ethoxyethoxy)-α-methylphenethyl]-amino]methyl]-2-pyridimidinemethanol;(R)-6-chloro-α[[[(S)-2-(6-chloro-2-pyridyl)-2-hydroxyethyl][(R)-.alpha.-methyl-p-(2-phenethoxyethoxy)phenethyl]amino]methyl]-2-pyridinemethanol.

In some embodiments, the CYP51A1 inhibitor is a compound represented byformula (II)

wherein n is an integer from 1 to 4 and m is an integer from 0 to 5;

R₁ is a hydrogen atom, hydroxyl group, or lower C₁₋₆ alkoxy group;

R₂ is a hydrogen atom or an optionally substituted straight or branchedlower C₁₋₆ alkyl group (e.g., an aryl lower alkyl group, such as aphenyl lower alkyl group); and

each X is independently fluorine, chlorine, bromine, hydroxyl group,trifluoromethyl group, 3,4-di-Cl, 2,4-di-Cl or lower C₁₋₆ alkoxy group,and wherein the phenyl ring containing the X is optionally fused (so asto form, e.g., a naphthyl ring);

or a pharmaceutically acceptable salt, ester, or ether thereof.

In some embodiments, the CYP51A1 inhibitor is a compound represented byformula (1), (2), (3), (13), (14), (15), or (16), or a pharmaceuticallyacceptable salt, ester, or ether thereof.

In some embodiments, n is an integer 2, R₁ is a hydroxyl group, R₂ amethyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl group and X is ahydrogen atom or phenyl disubstituted with 2 chlorine atoms in thepositions 3 and 4 or in the positions 2 and 4.

Exemplary variants of LEK-935 that may be used in conjunction with thecompositions and methods described herein are those compounds describedin U.S. Pat. Nos. 4,800,206 and 7,560,474, the disclosures of each ofwhich are incorporated herein by reference in their entirety.

CP-320626 and Variants Thereof

In some embodiments, the CYP51A1 inhibitor is CP-320626, represented byformula (4) herein.

In some embodiments, the CYP51A1 inhibitor is a variant of CP-320626that retains CYP51A1 inhibitory activity, such as a compound representedby formula (III)

wherein the dotted line (

) is an optional bond;

X is O or S;

A is —C(H)═, —C((C₁-C₄)alkyl)═, —C(halo)═ or —N═, when the dotted line (

) is a bond, or A is methylene or —CH((C₁-C₄)alkyl)—, when the dottedline (

) is not a bond;

R₁, R₁₀ or R₁₁ are each independently H, halo, cyano, 4-, 6-, or7-nitro, (C₁-C₄)alkyl, (C₁-C₄)alkoxy, fluoromethyl, difluoromethyl ortrifluoromethyl;

R₂ is H;

R₃ is H or (C₁-C₆)alkyl;

R₄ is H, methyl, ethyl, n-propyl, hydroxy(C₁-C₃)alkyl,(C₁-C₃)alkoxy(C₁-C₃)alkyl, phenyl(C₁-C₄)alkyl,phenylhydroxy(C₁-C₄)alkyl, (phenyl)((C₁-C₄)-alkoxy)(C₁-C₄)alkyl,thien-2- or -3-yl(C₁-C₄)alkyl or fur-2- or 3-yl(C₁-C₄)alkyl wherein theR₄ rings are mono-, di- or tri-substituted independently on carbon withH, halo, (C₁-C₄)alkyl, (C₁-C₄)alkoxy, trifluoromethyl, hydroxy, amino,cyano or 4,5-dihydro-1H-imidazol-2-yl; or

R₄ is pyrid-2-, -3- or -4-yl(C₁-C₄)alkyl, thiazol-2-, -4- or-5-yl(C₁-C₄)alkyl, imidazol-2-, -4- or -5-yl(C₁-C₄)alkyl, pyrrol-2- or-3-yl(C₁-C₄)alkyl, oxazol-2-, -4- or -5-yl(C₁-C₄)alkyl, pyrazol-3-, -4-or -5-yl(C₁-C₄)alkyl, isoxazol-3-, -4- or -5-yl(C₁-C₄)alkyl,isothiazol-3-, -4- or -5-yl(C₁-C₄)alkyl, pyridazin-3- or-4-yl(C₁-C₄)alkyl, pyrimidin-2-, -4-, -5- or -6-yl(C₁-C₄)alkyl,pyrazin-2- or -3-yl(C₁-C₄)alkyl, 1,3,5-triazin-2-yl(C₁-C₄)alkyl; orindol-2-(C₁-C₄)alkyl, wherein the preceding R₄ heterocycles areoptionally mono- or di-substituted independently with halo,trifluoromethyl, (C₁-C₄)alkyl, (C₁-C₄)alkoxy, amino, hydroxy or cyanoand the substituents are bonded to carbon; or

R₄ is R₁₅-carbonyloxymethyl, wherein the R₁₅ is phenyl, thiazolyl,imidazolyl, 1H-indolyl, furyl, pyrrolyl, oxazolyl, pyrazolyl,isoxazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinylor 1,3,5-triazinyl and wherein the preceding R₁₅ rings are optionallymono- or di-substituted independently with halo, amino, hydroxy,(C₁-C₄)alkyl, (C₁-C₄)alkoxy or trifluoromethyl and the mono- ordi-substituents are bonded to carbon;

R₅ is H, methyl, ethyl, n-propyl, hydroxymethyl or hydroxyethyl;

R₆ is carboxy, (C₁-C₈)alkoxycarbonyl, benzyloxycarbonyl, C(O)NR₈R₉ orC(O)R₁₂ wherein

R₈ is H, (C₁-C₆)alkyl, cyclo(C₃-C₆)alkyl, cyclo(C₃-C₆)alkyl(C₁-C₅)alkyl,hydroxy or (C₁-C₈)alkoxy; and

R₉ is H, cyclo(C₃-C₈)alkyl, cyclo(C₃-C₈)alkyl(C₁-C₅)alkyl,cyclo(C₄-C₇)alkenyl, cyclo(C₃-C₇)alkyl(C₁-C₅)alkoxy,cyclo(C₃-C₇)alkyloxy, hydroxy, methylene-perfluorinated(C₁-C₈)alkyl,phenyl, or a heterocycle wherein the heterocycle is pyridyl, furyl,pyrrolyl, pyrrolidinyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl,pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl, pyranyl,pyridinyl, piperidinyl, morpholinyl, pyridazinyl, pyrimidinyl,pyrazinyl, piperazinyl, 1,3,5-triazinyl, benzothiazolyl, benzoxazolyl,benzimidazolyl, thiochromanyl or tetrahydrobenzothiazolyl wherein theheterocycle rings are carbon-nitrogen linked; or

R₉ is (C₁-C₆)alkyl or (C₁-C₈)alkoxy wherein the (C₁-C₆)alkyl or(C₁-C₈)alkoxy is optionally monosubstituted with cyclo(C₄-C₇)alken-1-yl,phenyl, thienyl, pyridyl, furyl, pyrrolyl, pyrrolidinyl, oxazolyl,thiazolyl, imidazolyl, pyrazolyl, pyrazolinyl, pyrazolidinyl,isoxazolyl, isothiazolyl, pyranyl, piperidinyl, morpholinyl,thiomorpholinyl, 1-oxothiomorpholinyl, 1,1-dioxothiomorpholinyl,pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, 1,3,5-triazinyl orindolyl and wherein the (C₁-C₆)alkyl or (C₁-C₈)alkoxy are optionallyadditionally independently mono- or di-substituted with halo, hydroxy,(C₁-C₅)alkoxy, amino, mono-N— or di-N,N—(C₁-C₅)alkylamino, cyano,carboxy, or (C₁-C₄)alkoxycarbonyl; and

wherein the R₉ rings are optionally mono- or di-substitutedindependently on carbon with halo, (C₁-C₄)alkyl, (C₁-C₄)alkoxy, hydroxy,hydroxy(C₁-C₄)alkyl, amino(C₁-C₄)alkyl, mono-N— ordi-N,N—(C₁-C₄)alkylamino(C₁-C₄)alkyl, (C₁-C₄)alkoxy(C₁-C₄)alkyl, amino,mono-N— or di-N,N—(C₁-C₄)alkylamino, cyano, carboxy,(C₁-C₅)alkoxycarbonyl, carbamoyl, formyl or trifluoromethyl and the R₉rings may optionally be additionally mono- or di-substitutedindependently with (C₁-C₅)alkyl or halo;

with the proviso that no quaternized nitrogen on any R₉ heterocycle isincluded;

R₁₂ is morpholino, thiomorpholino, 1-oxothiomorpholino,1,1-dioxothiomorpholino, thiazolidin-3-yl, 1-oxothiazolidin-3-yl,1,1-dioxothiazolidin-3-yl, pyrrolidin-1-yl, piperidin-1-yl,piperazin-1-yl, piperazin-4-yl, azetidin-1-yl, 1,2-oxazinan-2-yl,pyrazolidin-1-yl, isoxazolidin-2-yl, isothiazolidin-2-yl,1,2-oxazetidin-2-yl, oxazolidin-3-yl, 3,4dihydroisoquinolin-2-yl,1,3-dihydrolsoindol-2-yl, 3,4-dihydro-2H-quinol-1-yl,2,3-dihydro-benzo[1,4]oxazin-4-yl, 2,3-dihydro-benzo[1,4]-thiazine-4-yl,3,4-dihydro-2H-quinoxalin-1-yl, 3,4-dihydro-benzo[c][1,2]oxazin-1-yl,1,4-dihydro-benzo[d][1,2]oxazin-3-yl,3,4-dihydro-benzo[e][1,2]-oxazin-2-yl, 3H-benzo[d]isoxazol-2-yl,3H-benzo[c]isoxazol-1-yl or azepan-1-yl,

wherein the R₁₂ rings are optionally mono-, di- or tri-substitutedindependently with halo, (C₁-C₅)alkyl, (C₁-C₅)alkoxy, hydroxy, amino,mono-N— or di-N,N—(C₁-C₅)alkylamino, formyl, carboxy, carbamoyl, mono-N—or di-N,N—(C₁-C₅)alkylcarbamoyl, (C₁-C₆)alkoxy(C₁-C₃)alkoxy,(C₁-C₅)alkoxycarbonyl, benzyloxycarbonyl,(C₁-C₅)alkoxycarbonyl(C₁C₅)alkyl, (C₁C₄)alkoxycarbonylamino,carboxy(C₁-C₅)alkyl, carbamoyl(C₁-C₅)alkyl, mono-N— ordi-N,N—(C₁-C₅)alkylcarbamoyl(C₁-C₅)alkyl, hydroxy(C₁-C₅)alkyl,(C₁-C₄)alkoxy(C₁₋₄)alkyl, amino(C₁C₄)alkyl, mono-N— ordi-N,N—(C₁-C₄)alkylamino(C₁-C₄)alkyl, oxo, hydroxylmino or(C₁-C₆)alkoxylmino and wherein no more than two substituents areselected from oxo, hydroxylmino or (C₁-C₆)alkoxylmino and oxo,hydroxylmino or (C₁-C₆)alkoxyimino are on nonaromatic carbon; and

the R₁₂ rings are optionally additionally mono- or di-substitutedindependently with (C₁-C₅)alkyl or halo.

In some embodiments of formula (III), when R₆ is (C₁-C₅)alkoxycarbonylor benzyloxycarbonyl then R₁ is 5-halo, 5-(C₁-C₄)alkyl or 5-cyano and R₄is (phenyl)(hydroxy)(C₁-C₄)alkyl, (phenyl)((C₁-C₄)alkoxy)(C₁-C₄)alkyl,hydroxymethyl or Ar(C₁-C₂)alkyl, wherein Ar is thien-2- or -3-yl, fur-2-or -3-yl or phenyl wherein the Ar is optionally mono- or di-substitutedindependently with halo; with the provisos that when R₄ is benzyl and R₅is methyl, R₁₂ is not 4-hydroxy-piperidin-1-yl or when R₄ is benzyl andR₅ is methyl R₆ is not C(O)N(CH₃)₂.

In some embodiments of formula (III), when R₁, R₁₀, and R₁₁ are H, R₄ isnot imidazol-4-ylmethyl, 2-phenylethyl or 2-hydroxy-2-phenylethyl.

In some embodiments of formula (III), when both R₈ and R₉ are n-pentyl,none of R₁ is 5-chloro, 5-bromo, 5-cyano, 5(C₁-C₅)alkyl, 5(C₁-C₅)alkoxyor trifluoromethyl.

In some embodiments of formula (III), when R₁₂ is3,4dihydroisoquinol-2-yl, the 3,4-dihydroisoquinol-2-yl is notsubstituted with carboxy((C₁-C₄)alkyl.

In some embodiments of formula (III), when R₈ is H and R₉ is(C₁-C₆)alkyl, R₉ is not substituted with carboxy or(C₁-C₄)alkoxycarbonyl on the carbon which is attached to the nitrogenatom N of NHR₉.

In some embodiments of formula (III), when R₆ is carboxy and R₁, R₁₀,R₁₁ and R₅ are all H, then R₄ is not benzyl, H, (phenyl)(hydroxy)methyl,methyl, ethyl or n-propyl.

Exemplary compounds of formula (III) are those belonging to a firstgroup of compounds in which:

R₁ is 5H, 5-halo, 5-methyl, 5-cyano or 5-trifluoromethyl;

R₁₀ and R₁₁ are each independently H or halo;

A is —C(H)═;

R₂ and R₃ are H;

R₄ is H, methyl, phenyl(C₁C₂)alkyl, wherein the phenyl groups are mono-or di-substituted independently with H, halo, (C₁-C₄)alkyl,(C₁C₄)alkoxy, trifluoromethyl, hydroxy, amino or cyano and wherein theR₄ groups are optionally additionally mono-substituted with halo; or

R₄ is thien-2- or -3-yl(C₁-C₂)alkyl, pyrid-2-, -3- or -4-yl(C₁-C₂)alkyl,thiazol-2-, -4- or -5-yl(C₁-C₂)alkyl, imidazol-2-, -4- or-5-yl(C₁-C₂)alkyl, fur-2- or -3-yl(C₁-C₂)alkyl, pyrrol-2- or-3-yl(C₁-C₂)alkyl, oxazol-2-, -4- or -5-yl(C₁-C₂)alkyl, pyrazol-3-, -4-or -5-yl(C₁-C₂)alkyl, isoxazol-3-, -4- or -5-yl(C₁-C₂)alkyl,isothiazol-3-, -4- or -5-yl(C₁-C₂)alkyl, pyridazin-3- or-4-yl(C₁-C₂)alkyl, pyrimidin-2-, -4-, -5- or -6-yl(C₁-C₂)alkyl,pyrazin-2- or -3-yl(C₁-C₂)alkyl or 1,3,5-triazin-2-yl(C₁-C₂)alkylwherein the preceding R₄ heterocycles are optionally mono- ordi-substituted independently with halo, trifluoromethyl, (C₁-C₄)alkyl,(C₁-C₄)alkoxy, amino or hydroxy and the mono- or di-substituents arebonded to cabin;

R₅ is H; and

R₆ is C(O)NR₈R₉ or C(O)R₁₂.

For example, compounds of formula (III) that may be used in conjunctionwith the compositions and methods described herein include those inwhich:

R₄ is H, phenyl(C₁-C₂)alkyl, thien-2- or -3-yl(C₁-C₂)alkyl, fur-2- or-3-yl(C₁-C₂)alkyl wherein the R₄ rings are mono- or di-substitutedindependently with H or fluoro;

R₆ is C(O)R₁₂; and

R₁₂ is morpholino, thiomorpholino, 1-oxothiomorpholino,1,1-dioxothiomorpholino, thiazolidin-3-yl, 1-oxothiazolidin-3-yl,1,1-dioxothiazolidin-3-yl, pyrrolidin-1-yl, piperidin-1-yl,piperazin-1-yl, piperazin-4-yl, azetidin-1-yl, 1,2oxazinan-2-yl,isoxazolidin-2-yl, isothiazolidin-2-yl, 1,2-oxazetidin-2-yl,oxazolidin-3-yl, 1,3-dihydroisoindol-2-yl, or azepan-1-yl,

the R₁₂ rings are optionally mono- or di-substituted independently withhalo, (C₁-C₅)alkyl, (C₁-C₅)alkoxy, hydroxy, amino, mono-N— ordi-N,N—(C₁-C₅)alkylamino, formyl, carboxy, carbamoyl, mono-N— ordi-N,N—(C₁-C₅)alkylcarbamoyl, (C₁-C₅)alkoxycarbonyl,hydroxy(C₁-C₅)alkyl, amino(C₁-C₄)alkyl, mono-N— ordi-N,N—(C₁C₄)alkylamino(C₁-C₄)alkyl, oxo, hydroxylmino or(C₁-C₆)alkoxylmino with the proviso that only the R₁₂ heterocyclesthiazolidin-3-yl, pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl,piperazin-4-yl, azetidin-1-yl, 1,2-oxazinan-2-yl, isoxazolidin-2-yl, oroxazolidin-3-yl are optionally mono- or di-substituted with oxo,hydroxylmino, or (C₁-C₆)alkoxylmino; and

the R₁₂ rings are optionally additionally mono- or di-substitutedindependently with (C₁-C₅)alkyl.

Further exemplary compounds of formula (III) that may be used inconjunction with the compositions and methods described herein include:5-Chloro-1H-indole-2-carboxylic acid[(1S)-benzyl-2-(3-hydroxylmino-pyrrolidin-1-yl)-2-oxo-ethyl]-amide,5-Chloro-1H-indole-2-carboxylic acid[2-(cis-3,4-dihydroxy-pyrrolidin-1-yl)-2-oxo-ethyl]amide,5-Chloro-1H-indole-2-carboxylic acid[2-((3S,4S)-dihydroxy-pyrrolidin-1-yl)-2-oxo-ethyl]amide,5-Chloro-1H-indole-2-carboxylic acid[(1S)-benzyl-2-(cis-3,4-dihydroxy-pyrrolidin-1-yl)-2-oxo-ethyl]-amide,5-Chloro-1H-indole-2-carboxylic acid[2-(1,1-dioxo-thiazoildin-3-yl)-2-oxo-ethyl]amide,5-Chloro-1H-indole-2-carboxylic acid(2-oxo-2-thiazolidin-3-yl-ethyl)-amide, 5-Chloro-1H-indole-2-carboxylicacid[(1S)-(4-fluoro-benzyl)-2-(4-hydroxy-piperidin-1-yl)-2-oxo-ethyl]amide,5-Chloro-1H-indole-2-carboxylic acid[(1S)-benzyl-2-((3RS)-hydroxy-piperidin-1-yl)-2-oxo-ethyl]-amide,5Chloro-1H-indole-2-carboxylic acid[2-oxo-2-((1RS)-oxo-1-thiazolidin-3-yl)-ethyl]-amide,5-Chloro-1H-indole-2-carboxylic acid[(1S)-(2-fluoro-benzyl)-2-(4-hydroxy-piperidin-1-yl)-2-oxo-ethyl]-amide,5-Chloro-1H-indole-2-carboxylic acid[(1S)-benzyl-2-((3S,4S)-dihydroxy-pyrrolidin-1-yl)-2-oxo-ethyl]-amide,5-Chloro-1H-indole-2-carboxylic acid[(1S)-benzyl-2-(3-hydroxy-azetidin-1-yl)-2-oxo-ethyl]amide,5-Chloro-1H-indole-2-carboxylic acid[(1S)-benzyl-2-(3-hydroxyimino-azetidin-1-yl)-2-oxo-ethyl]-amide, and5-Chloro-1H-indole-2-carboxylic acid[(1S)-benzyl-2-(4-hydroxyimino-piperidin-1-yl)-2-oxo-ethyl]-amide.

Further exemplary compounds of formula (III) that may be used inconjunction with the compositions and methods described herein includethose in which:

R₄ is H; and

R₁₂ is thiazolidin-3-yl, 1-oxo-thiazolidin-3-yl,1,1-dioxo-thiazolidin-3-yl or oxazolidin-3-yl or the R₁₂ substituentsoptionally mono- or di-substituted independently with carboxy,(C₁-C₅)alkoxycarbonyl, hydroxy(C₁-C₃)alkyl, amino(C₁-C₃)alkyl, mono-N—or di-N,N—(C₁-C₃)alkylamino(C₁-C₃)alkyl or

R₁₂ is mono- or di-substituted pyrrolidin-1-yl wherein the substituentsare independently carboxy, (C₁-C₅)alkoxycarbonyl, (C₁-C₅)alkoxy,hydroxy, hydroxy(C₁-C₃)alkyl, amino, amino(C₁-C₃)alkyl, mono-N— ordi-N,N—(C₁-C₃)alkylamino(C₁-C₃)alkyl or mono-N— ordi-N,N—(C₁-C₄)alkylamino; and the R₁₂ rings are optionally additionallyindependently disubstituted with (C₁-C₅)alkyl.

Further exemplary compounds of formula (III) that may be used inconjunction with the compositions and methods described herein includethose in which:

(a) R₁ is 5-chloro;

R₁₀ and R₁₁ are H; and

R₁₂ is cis-3,4-dihydroxy-pyrrolidin-1-yl;

(b) R₁ is 5-chloro;

R₁₀ and R₁₁ are H; and

R₁₂ is (3S,4S)-dihydroxy-pyrrolidin-1-yl;

(c) R₁ is 5-chloro;

R₁₀ and R₁₁ are H; and

R₁₂ is 1,1-dioxo-thiazolidin-3-yl;

(d) R₁ is 5-chloro;

R₁₀ and R₁₁ are H; and

R₁₂ is thiazolidin-3-yl; and

(e) R₁ is 5-chloro;

R₁₀ and R₁₁ are H; and

R₁₂ is 1-oxo-thiazolidin-3-yl.

Further exemplary compounds of formula (III) that may be used inconjunction with the compositions and methods described herein includethose in which:

R₄ is phenylmethyl, thien-2- or -3-ylmethyl wherein the R₄ rings areoptionally mono- or di-substituted with fluoro; and

R₁₂ is thiazolidin-3-yl, 1-oxo-thiazolidin-3-yl,1,1-dioxo-thiazolidin-3-yl or oxazolidin-3-yl or the R₁₂ substituentsoptionally mono- or di-substituted independently with carboxy or(C₁-C₅)alkoxycarbonyl, hydroxy(C₁-C₃)alkyl, amino(C₁-C₃)alkyl or mono-N—or di-N,N—(C₁-C₃)alkylamino(C₁-C₃)alkyl or

R₁₂ is mono- or di-substituted azetidin-1-yl or mono- or di-substitutedpyrrolidin-1-yl or mono- or di-substituted piperidin-1-yl wherein thesubstituents are independently carboxy, (C₁-C₅)alkoxycarbonyl,hydroxy(C₁-C₃)alkyl, amino(C₁-C₃)alkyl, mono-N— ordi-N,N—(C₁-C₃)alkylamino(C₁-C₃)alkyl, hydroxy, (C₁-C₅)alkoxy, amino,mono-N— or di-N,N—(C₁-C₅)alkylamino, oxo, hydroxylmino or(C₁-C₅)alkoxylmino; and

the R₁₂ rings are optionally additionally mono- or di-substitutedindependently with (C₁-C₅)alkyl.

Further exemplary compounds of formula (III) that may be used inconjunction with the compositions and methods described herein includethose in which:

(a) R₁ is 5-chloro;

R₁₀ and R₁₁ are H;

R₄ is 4-fluorobenzyl;

R₁₂ is 4-hydroxypiperidin-1-yl; and

the stereochemistry of carbon (a) is (S);

(b) R₁ is 5-chloro;

R₁₀ and R₁₁ are H;

R₄ is benzyl;

R₁₂ is 3-hydroxypiperidin-1-yl; and

the stereochemistry of carbon (a) is (S);

(c) R₁ is 5-chloro;

R₁₀ and R₁₁ are H;

R₄ is benzyl;

R₁₂ is cis-3,4-dihydroxy-pyrrolidin-1-yl; and

the stereochemistry of carbon (a) is S;

(d) R₁ is 5-chloro;

R₁₀ and R₁₁ are H; R₄ is benzyl;

R₁₂ is 3-hydroxyimino-pyrrolidin-1-yl; and

the stereochemistry of carbon (a) is (S);

(e) R₁ is 5-chloro;

R₁₀ and R₁₁ are H;

R₄ is 2-fluorobenzyl;

R₁₂ is 4-hydroxypiperidin-1-yl; and

the stereochemistry of carbon (a) is (S);

(f) R₁ is 5-chloro;

R₁₀ and R₁₁ are H;

R₄ is benzyl;

R₁₂ is (3S,4S)-dihydroxy-pyrrolidin-1-yl; and

the stereochemistry of carbon (a) is (S);

(g) R₁ is 5-chloro;

R₁₀ and R₁₁ are H;

R₄ is benzyl;

R₁₂ is 3-hydroxy-azetidin-1-yl; and

the stereochemistry of carbon (a) is (S);

(h) R₁ is 5-chloro;

R₁₀ and R₁₁ are H;

R₄ is benzyl;

R₁₂ is 3-hydroxyimino-azetidin-1-yl; and

the stereochemistry of carbon (a) is (S); and

(i) R₁ is 5chloro;

R₁₀ and R₁₁ are H;

R₄ is benzyl;

R₁₂ is 4-hydroxyimino-piperidin-1-yl; and

the stereochemistry of carbon (a) is (S).

Additionally, exemplary compounds of formula (III) are those belongingto a second group of compounds in which:

R₄ is H, phenyl(C₁-C₂)alkyl, thien-2- or -3-yl(C₁-C₂)alkyl, fur-2- or-3-yl(C₁-C₂)alkyl wherein the R₄ rings are mono- or di-substitutedindependently with H or fluoro;

R₆ is C(O)NR₈R₉; and

R₈ is H, (C₁-C₅)alkyl, hydroxy or (C₁-C₄)alkoxy; and

R₉ is H, cyclo(C₄-C₆)alkyl, cyclo(C₃-C₆)alkyl(C₁-C₅)alkyl,methylene-perfluorinated(C₁-C₃)alkyl, pyridyl, pyrrolidinyl, oxazolyl,thiazolyl, imidazolyl, piperidinyl, benzothiazolyl or thiochromanyl; orR₉ is (C₁-C₅)alkyl wherein the (C₁-C₅)alkyl is optionally substitutedwith cyclo(C₄-C₆)alkenyl, phenyl, thienyl, pyridyl, pyrrolidinyl,oxazolyl, thiazolyl, imidazolyl, pyrazolyl, piperidinyl, morpholinyl,thiomorpholinyl, 1-oxothiomorpholinyl, or 1,1-dioxothiomorpholinyl andwherein the (C₁-C₅)alkyl or (C₁-C₄)alkoxy is optionally additionallyindependently mono- or di-substituted with halo, hydroxy, (C₁-C₅)alkoxy,amino, mono-N— or di-N,N—(C₁-C₅)alkylamino, cyano, carboxy, or(C₁-C₄)alkoxycarbonyl; wherein the R₉ rings are optionally mono- ordi-substituted independently on carbon with halo, (C₁-C₄)alkyl,(C₁-C₄)alkoxy, hydroxy, amino, mono-N— or di-N,N—(C₁-C₄)alkylamino,carbamoyl, (C₁-C₅)alkoxycarbonyl or carbamoyl.

Further exemplary compounds of formula (III) that may be used inconjunction with the compositions and methods described herein includethose in which:

(a) R₁ is 5-chloro;

R₁₀ and R₁₁ are H;

R₄ is benzyl;

R₈ is methyl; and

R₉ is 3-(dimethylamino)propyl;

(b) the stereochemistry of carbon (a) is (S);

R₁ is 5-chloro;

R₁₀ and R₁₁ are H;

R₄ is benzyl;

R₈ is methyl; and

R₉ is 3-pyridyl;

(c) the stereochemistry of carbon (a) is (S);

R₁ is 5-chloro;

R₁₀ and R₁₁ are H;

R₄ is benzyl;

R₈ is methyl; and

R₉ is 2-hydroxyethyl; and

(d) the stereochemistry of carbon (a) is (S);

R₁ is 5-fluoro;

R₁₀ and R₁₁ are H;

R₄ is 4-fluorophenylmethyl;

R₈ is methyl; and

R₉ is 2-morpholinoethyl.

Additionally, exemplary compounds of formula (III) are those belongingto a third group of compounds in which:

R₄ is H, phenyl(C₁-C₂)alkyl, thien-2- or -3-yl(C₁-C₂)alkyl, fur-2- or-3-yl(C₁-C₂)alkyl wherein the R₄ rings are mono- or di-substitutedindependently with H or fluoro;

R₆ is C(O)NR₈R₉; and

R₈ is H, (C₁-C₅)alkyl, hydroxy or (C₁-C₄)alkoxy; and

R₉ is (C₁-C₄)alkoxy wherein the (C₁-C₄)alkoxy is optionally substitutedwith cyclo(C₄-C₆)alkenyl, phenyl, thienyl, pyridyl, pyrrolidinyl,oxazolyl, thiazolyl, imidazolyl, pyrazolyl, piperidinyl, morpholinyl,thiomorpholinyl, 1-oxothiomorpholinyl, or 1,1-dioxothiomorpholinyl andwherein the (C₁-C₅)alkyl or (C₁-C₄)alkoxy is optionally additionallyindependently mono- or di-substituted with halo, hydroxy, (C₁-C₅)alkoxy,amino, mono-N— or di-N,N—(C₁-C₅)alkylamino, cyano, carboxy, or(C₁-C₄)alkoxycarbonyl; wherein the R₉ rings are optionally mono- ordi-substituted independently on carbon with halo, (C₁-C₄)alkyl,(C₁-C₄)alkoxy, hydroxy, amino, mono-N— or di-N,N—(C₁-C₄)alkylamino,carbamoyl, (C₁-C₅)alkoxycarbonyl or carbamoyl.

Further exemplary compounds of formula (III) that may be used inconjunction with the compositions and methods described herein includethose in which:

(a) R₁ is 5-chloro;

R₁₀ and R₁₁ are H;

R₄ is benzyl;

R₈ is methyl; and

R₉ is 2-hydroxyethoxy;

(b) the stereochemistry of carbon (a) is (S);

R₁ is 5-chloro;

R₁₀ and R₁₁ are H;

R₄ is 4-fluorophenylmethyl;

R₈ is methyl; and

R₉ is methoxy;

(c) the stereochemistry of carbon (a) is (S);

R₁ is 5-chloro;

R₁₀ and R₁₁ are H;

R₄ is benzyl;

R₈ is methyl; and

R₉ is methoxy;

Further exemplary compounds of formula (III) that may be used inconjunction with the compositions and methods described herein includethose in which:

R₁ is 5-halo, 5-methyl, 5-cyano or trifluoromethyl;

R₁₀ and R₁₁ are each independently H or halo;

A is —C(H)═;

R₂ and R₃ are H;

R₄ is H, phenyl(C₁-C₂)alkyl, thien-2- or -3-yl(C₁-C₂)alkyl, fur-2- or3-yl(C₁-C₂)alkyl wherein the rings are mono- or di-substitutedIndependently with H or fluoro;

R₅ is H; and

R₆ is (C₁-C₅)alkoxycarbonyl.

Further exemplary compounds of formula (III) that may be used inconjunction with the compositions and methods described herein includethose in which:

R₁ is 5-halo, 5-methyl, 5-cyano or trifluoromethyl;

R₁₀ and R₁₁ are each independently H or halo;

A is —C(H)═;

R₂ and R₃ are H;

R₄ is H, methyl or phenyl(C₁-C₂)alkyl, wherein the phenyl groups aremono- or di-substituted independently with H, halo, (C₁-C₄)alkyl,(C₁-C₄)alkoxy, trifluoromethyl, hydroxy, amino or cyano and wherein thephenyl groups are additionally mono- or di-substituted independently Hor halo; or

R₄ is thien-2- or -3yl(C₁-C₂)alkyl, pyrid-2-, -3- or -4-yl(C₁-C₂)alkyl,thiazol-2-, -4- or -5-yl(C₁-C₂)alkyl, imidazol-2-, -4- or-5-yl(C₁-C₂)alkyl, fur-2- or -3-yl(C₁-C₂)alkyl, pyrrol-2- or-3-yl(C₁-C₂)alkyl, oxazol-2-, -4- or -5-yl(C₁-C₂)alkyl, pyrazol-3-, -4-or -5-yl(C₁-C₂)alkyl, isoxazol-3-, -4- or -5-yl(C₁-C₂)alkyl,isothiazol-3-, -4- or -5-yl(C₁-C₂)alkyl, pyridazin-3- or-4yl(C₁-C₂)alkyl, pyrimidin-2-, -4-, -5- or -6-yl(C₁-C₂)alkyl,pyrazin-2- or -3-yl(C₁-C₂)alkyl or 1,3,5-triazin-2-yl(C₁-C₂)alkylwherein the preceding R₄ heterocycles are optionally mono- ordi-substituted independently with halo, trifluoromethyl, (C₁-C₄)alkyl,(C₁-C₄)alkoxy, amino or hydroxy and the mono- or di-substituents arebonded to carbon;

R₅ is H; and

R₆ is carboxy.

Further exemplary compounds of formula (III) that may be used inconjunction with the compositions and methods described herein includethose in which:

R₁₀ and R₁₁ are H; and

R₄ is H.

Further exemplary compounds of formula (III) that may be used inconjunction with the compositions and methods described herein includethose in which R₁ is 5-chloro.

Exemplary variants of CP-320606 that may be used in conjunction with thecompositions and methods described herein are those compounds describedin U.S. Pat. No. 6,277,877, the disclosure of which is incorporatedherein by reference in its entirety.

Itraconazole, Posaconazole, and Variants Thereof

In some embodiments, the CYP51A1 inhibitor itraconazole, posaconazole,or a variant thereof that retains CYP51A1 inhibitory activity. Forexample, the CYP51A1 inhibitor may be a compound represented by formula(IV)

wherein Ar is thienyl, pyridyl, biphenyl, phenyl or phenyl substitutedby one or more of halo, nitro, cyano, lower alkyl, lower alkoxy orperhalo(lower)alkyl;

Y is CH or N;

either one of A, B and C is oxygen and the remaining two of A, B and Care CH₂; or A is oxygen, B is CH₂, and C is a direct bond;

Q is:

W is —NR₅—, —O—, or —S(O)_(n)—;

X is —NO₂, —P—NR₆R₇,

Ar, OR₃ or halogen;

P is a direct bond, —CHR₁₁— or —CHR₁₁CHR₁₂—;

R₁, R₈, R₉ and R₁₀ are independently hydrogen, lower alkyl or loweralkyl substituted by one or more hydroxy groups;

R₂, R₄, R₁₁, R₁₂ and R₁₄ are hydrogen, hydroxy, lower alkyl or loweralkyl substituted by one or more hydroxy groups;

R₃ and R₁₃ are independently hydrogen, lower alkyl, (C₂-C₈)perhaloalkanoyl or (C₂-C₈) alkanoyl;

R₆ and R₇ are independently hydrogen, lower alkyl, phenyl or phenylsubstituted by one or more of halo, perhalo(lower)alkyl,(C₂-C₈)alkanoyl, lower alkyl, lower alkyl substituted by one or morehydroxy groups, lower alkoxy, or2-(lower)alkyl-3-oxo-1,2,4-triazol-4-yl, or R₆ and R₇ taken togetherwith the nitrogen atom in NR₆ R₇ form unsubstituted or substituted 5- or6-membered heterocyclyl ring systems containing carbon and one to fourheteroatoms chosen from N, O and S, the heterocyclyl substituents being(C₁-C₈)alkanoyl, lower alkyl, lower alkoxycarbonyl, aminocarbonyl,N-lower alkylaminocarbonyl, N,N-di(lower alkyl)amino carbonyl,aminothiocarbonyl, N-lower alkylaminothiocarbonyl, N,N-di(loweralkyl)aminothiocarbonyl, lower alkyl sulfonyl, phenyl-substituted loweralkyl sulfonyl, N-lower alkylamino, N,N-di(lower alkyl)amino,1,3-imidazol-1-yl, 2-loweralkylsulfenyl-1,3-imidazol-1-yl, 2-pyridinyl,2-thiazolyl, 2-lower alkyl-3-oxo-1,2,4-triazol-4-yl, 1-loweralkylbenzimidazol-2-yl, phenyl or phenyl substituted by one or more ofhalo, perhalo lower alkyl, (C₂-C₈) alkanoyl, lower alkyl, lower alkylsubstituted by one or more hydroxy group, lower alkoxy,1H,2,4-triazol-1-yl, 2-lower alkyl-3-oxo-1,2,4-triazol-4-yl, or asubstituent represented by the formula:

R₅ is a lower alkyl, lower alkoxy, amino, N,N-dilower alkylamino, phenylor phenyl substituted by one or more of halo, perhalo lower alkyl, loweralkoxy, nitro, cyano, (C₂-C₈)alkanoyl;

p is 0, 1, 2, 3, 4 or 5;

n is 0, 1 or 2;

r is 1 or 2; and

t is 0, 1, 2 or 3;

or a pharmaceutically acceptable salt, ester, or ether thereof.

In some embodiments of formula (IV), when R₂, R₁₁, or R₁₂ is attached toa carbon atom adjacent to —NR₅, —S(O)_(n) or —O—, the R₂, R₁₁, or R₁₂ isnot hydroxy.

In some embodiments, the CYP51A1 inhibitor is represented by formula (V)

Wherein Y and Ar are as defined for formula (IV) herein;

one of A, B or C is oxygen and the remaining two of A, B, or C are—CH₂—;

T is ═O, ═NOR₁, ═NNR₁ R₂ or

wherein R₁ is hydrogen, lower alkyl or lower alkyl substituted by one ormore hydroxy groups; and

R₂ is hydrogen, hydroxy, lower alkyl or lower alkyl substituted by oneor more hydroxy groups.

In some embodiments, the CYP51A1 inhibitor is represented by formula(VI)

wherein Y, Ar, R₁, R₂, R₆ and R₇ are as previously defined for formula(IV) herein, and either one of A, B and C is oxygen and the remainingtwo of A, B and C are CH₂, or A is oxygen, B is CH₂, and C is a directbond.

Exemplary compound of formula (VI) for use in conjunction with thecompositions and methods described herein are those in which NR₆ R₇ formunsubstituted or substituted 5- or 6-membered heterocyclyl ring systemscontaining carbon and one to four heteroatoms chosen from N, O and S,the heterocyclyl substituents being (C₁-C₈) alkanoyl, lower alkyl, loweralkoxycarbonyl, aminocarbonyl, N-lower alkylaminocarbonyl, N,N-di(loweralkyl)aminocarbonyl, aminothiocarbonyl, N-lower alkylaminothiocarbonyl,N,N-di(lower alkyl)aminothiocarbonyl, lower alkyl sulfonyl,phenyl-substituted lower alkyl sulfonyl, N-lower alkyl-amino,N,N-di(lower alkyl)amino, 1,3-imidazol-1-yl,2-loweralkylsulfenyl-1,3-imidazol-1-yl, 2-pyridinyl, 2-thiazolyl,2-lower alkyl-3-oxo-1,2,4-triazol-4-yl, 1-lower alkylbenzimidazol-2-yl,phenyl, phenyl substituted by one or more of halo, perhalo lower alkyl,(C₂-C₈)alkanoyl, lower alkyl, lower alkyl substituted by one or morehydroxy groups, lower alkoxy, 1H,2,4-triazol-1-yl or 2-loweralkyl-3-oxo-1,2,4-triazol-4-yl; R₅ is a lower alkyl, amino, N,N-diloweralkylamino, or

In some embodiments of formula (VI), the NR₆R₇ is:

wherein Z is hydrogen, (C₁-C₈) alkanoyl, lower alkyl, (C₁-C₈)perhaloalkanoyl or phenyl substituted by2-loweralkyl-3-oxo-1,2,4-triazol-4-yl.

In some embodiments, the CYP51A1 inhibitor is represented by formula(VII)

wherein one of A, B and C is oxygen and the remaining two of A, B and Care —CH₂—, or two of A, B and C are —CH₂—;

each Hal is independently a halogen, such as Cl or F; and

Z is lower alkyl, (C₂-C₈)alkanoyl, or phenyl substituted by2-loweralkyl-3-oxo-1,2,4triazol-4-yl.

In some embodiments of formula (VII), the compound is selected from:

In some embodiments, the CYP51A1 inhibitor is represented by formula(VIII)

wherein Ar is thienyl, pyridyl, biphenyl, phenyl or phenyl substitutedby one or more of halo, nitro, cyano, lower alkyl, lower alkoxy orperhalo(lower)alkyl;

Q is:

W is —NR₅—, —O—, or —S(O)_(n)—;

X is —NO₂, —P—NR₆R₇,

Ar, OR₃ or halogen;

P is a direct bond, —CHR₁₁— or —CHR₁₁CHR₁₂—;

R₈, R₉ and R₁₀ are independently hydrogen, lower alkyl or lower alkylsubstituted by one or more hydroxy groups;

R₄, R₁₁, R₁₂ and R₁₄ are hydrogen, hydroxy, lower alkyl or lower alkylsubstituted by one or more hydroxy groups;

R₃ and R₁₃ are independently hydrogen, lower alkyl, (C₂-C₈)perhaloalkanoyl or (C₂-C₈) alkanoyl;

R₆ and R₇ are independently hydrogen, lower alkyl, phenyl or phenylsubstituted by one or more of halo, perhalo(lower)alkyl,(C₂-C₈)alkanoyl, lower alkyl, lower alkyl substituted by one or morehydroxy groups, lower alkoxy, or2-(lower)alkyl-3-oxo-1,2,4-triazol-4-yl, or R₆ and R₇ taken togetherwith the nitrogen atom in NR₆ R₇ form unsubstituted or substituted 5- or6-membered heterocyclyl ring systems containing carbon and one to fourheteroatoms chosen from N, O and S, the heterocyclyl substituents being(C₁-C₈)alkanoyl, lower alkyl, lower alkoxycarbonyl, aminocarbonyl,N-lower alkylaminocarbonyl, N,N-di(lower alkyl)amino carbonyl,aminothiocarbonyl, N-lower alkylaminothiocarbonyl, N,N-di(loweralkyl)aminothiocarbonyl, lower alkyl sulfonyl, phenyl-substituted loweralkyl sulfonyl, N-lower alkylamino, N,N-di(lower alkyl)amino,1,3-imidazol-1-yl, 2-loweralkylsulfenyl-1,3-imidazol-1-yl, 2-pyridinyl,2-thiazolyl, 2-lower alkyl-3-oxo-1,2,4-triazol-4-yl, 1-loweralkylbenzimidazol-2-yl, phenyl or phenyl substituted by one or more ofhalo, perhalo lower alkyl, (C₂-C₈) alkanoyl, lower alkyl, lower alkylsubstituted by one or more hydroxy group, lower alkoxy,1H,2,4-triazol-1-yl, 2-lower alkyl-3-oxo-1,2,4-triazol-4-yl, or asubstituent represented by the formula:

R₅ is a lower alkyl, lower alkoxy, amino, N,N-dilower alkylamino, phenylor phenyl substituted by one or more of halo, perhalo lower alkyl, loweralkoxy, nitro, cyano, (C₂-C₈)alkanoyl;

p is 0, 1, 2, 3, 4 or 5;

n is 0, 1 or 2;

r is 1 or 2; and

t is 0, 1, 2 or 3;

R₁ is hydrogen, lower alkyl or lower alkyl substituted by one or morehydroxy groups; and

R₂ is hydrogen, hydroxy, lower alkyl or lower alkyl substituted by oneor more hydroxy groups.

In some embodiments, the CYP51A1 inhibitor is a compound represented byformula (IX)

wherein each X is independently a halogen, such as F or Cl; and

R₁ is a straight or branched chain (C₃ to C₈) alkyl group optionallysubstituted by one or two hydroxy moieties or by one or two groupsconvertible in vivo into hydroxy moieties;

or a pharmaceutically acceptable salt, ester, or ether thereof.

In some embodiments of formula (IX), the compound is represented byformula (X)

wherein each X is independently a halogen, such as F or Cl; and

R₂ is H or (C₁-C₃) alkyl and R₃ is (C₁-C₃) alkyl optionally substitutedby one hydroxy moiety or by a group convertible in vivo into a hydroxymoiety;

or a pharmaceutically acceptable salt, ester, or ether thereof.

In some embodiments of formula (X), the compound is represented byformula (XI)

wherein R₅ is:

or a pharmaceutically acceptable salt, ester, or ether thereof.

In some embodiments of formula (XI), the compound is represented byformula (XII)

wherein R₉ is —H(C₂H₅)CH(R₆)CH₃ or —H(CH₃)CH(R₆)CH₃;

R₆ is OH or a group convertible in vivo into OH;

or a pharmaceutically acceptable salt, ester, or ether thereof.

In some embodiments of formula (XII), the compound is:

or a pharmaceutically acceptable salt, ester, or ether thereof.

In some embodiments of formulas (IX)-(XII), the compound is an ester ofthe corresponding structural formula, such as a phosphate ester. Thephosphate ester may be, for example, a phosphate ester selected from

wherein z is 0 or 1, R₇ is a (C₁-C₆) straight or branched chain alkylgroup or H, f and n are independently an integer from 0 to 6, m is zeroor 1 and W is H, CH₂ Ar or and Ar is phenyl, phenyl substituted by halo,nitro, cyano or trihalomethyl.

Exemplary variants of itraconazole and posaconazole useful inconjunction with the compositions and methods described herein aredescribed in U.S. Pat. Nos. 5,039,676, and 5,661,151, the disclosures ofeach of which are incorporated herein by reference in their entirety.

Cyproconazole and Variants Thereof

In some embodiments, the CYP51A1 inhibitor cyproconazole or a variantthereof that retains CYP51A1 inhibitory activity, such as a compoundrepresented by formula (XIII)

wherein R_(O) is alkyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 6carbon atoms, cycloalkyl-alkyl in which the cycloalkyl is of 3 to 6carbon atoms and the alkyl portion of 1 to 3 carbon atoms, thecycloalkyl and cycloalkyl-alkyl being optionally ring substituted by oneor two alkyl groups of 1 to 3 carbon atoms;

R is hydrogen, fluoro, chloro, bromo, alkyl of 1 to 4 carbon atoms,alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms ornitro;

R′ is hydrogen, fluoro, chloro, bromo, alkyl of 1 to 4 carbon atoms,alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, —CF₃ inthe 3-position of Ring A, nitro, —CN, —COOR″, an optionally substitutedphenyl group of the formula:

or an optionally substituted phenoxy group in the 4-position of Ring Aand having the formula:

R″ is hydrogen, alkyl of 1 to 4 carbon atoms or a cation, preferably anagriculturally acceptable cation, or R and R′ together representalkylenedioxy of 1 or 2 carbon atoms substituted onto adjacent carbonatoms of the phenyl Ring A; and

Y_(O) and Y are independently hydrogen, fluoro, chloro, bromo, alkyl of1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms.

In some embodiments of formula (XIII), when R_(O) is n-butyl: (a) atleast one of R and R′ is other than hydrogen and (b) R and R′ are notboth halo.

In some embodiments, the CYP51A1 inhibitor is anα-[aryl(alkylene)_(m)]-α-[CR₁R₂—(CHR₃)_(n)—R₄]1H-1,2,4-triazole-1-ethanol(formula (XIV-A)) or anα-[aryl(alkylene)_(m)]-α-[CR₁R₂—(CHR₃)_(n)—R₄]1H-imidazole-1-ethanol(formula (XIV-B)), or a pharmaceutically acceptable salt or esterthereof, wherein:

R₁ is C₁₋₅ alkyl, unsubstituted or substituted by halogen, byC₁₋₅-alkoxy, by phenyl-C₁₋₃ alkoxy, by phenoxy, by C₁₋₅ alkylthio, byphenyl-C₁₋₃ alkylthio or by phenylthio, whereby optional phenyl groupsmay be substituted by C₁₋₅ alkyl, halogen, halogen substituted C₁₋₅alkyl, C₁₋₅ alkoxy or halogen substituted C₁₋₅ alkoxy; or

is C₂₋₅ alkenyl or C₂₋₅ alkynyl, unsubstituted or substituted byhalogen; or

is cycloalkyl, unsubstituted or substituted by C₁₋₅ alkyl; or

is phenyl, unsubstituted or substituted by substituents selected fromthe group consisting of halogen and C₁₋₅ alkyl;

R₂ and R₃, independently, are H or have an R₁ significance, whereby R₁and R₂ may be linked together to form a C₃₋₇ cycloalkyl group;

m is 0 or 1;

n is 0, 1 or 2; and

R₄ is C₃₋₇ cycloalkyl, unsubstituted or substituted by C₁₋₅ alkyl.

The aryl portion in the α-[aryl(alkylen)_(m)] moiety of formula (XIV)may be an aromatic hydrocarbon (e.g. naphthyl, preferably phenyl)unsubstituted or substituted, or a heteroaromatic ring linked by one ofits ring carbon atoms (e.g. a 5- or 6-membered ring with 1 or 2heteroatoms from the group O, N and S, preferably furyl, thienyl orpyridyl), and may be unsubstituted or substituted.

Examples of suitable α-[aryl(alkylene)_(m)] groups that may be presentin formula (XIV) are phenyl, benzyl and α-C₁₋₅ alkylbenzyl (e.g.,unsubstituted, mono- or multiple-substituted in the phenyl moiety byNO₂, halogen, C₁₋₅ alkyl, C₂₋₅ alkenyl, C₂₋₅ alkynyl, or C₁₋₅ alkoxy(unsubstituted or halogenated), phenyl, or phenoxy, unsubstituted orsubstituted). Further examples of suitable α-aryl groups are theheteroaromatic 3-pyridyl group and 2-thienyl and 2-furyl, which may be,for example, unsubstituted or singly substituted by halogen or loweralkyl (e.g. 5-Cl-2-thienyl and 5-tert.butyl-2-furyl).

For example, the α-[aryl(alkylene)_(m)] group may be phenyl, benzyl, orα-C₁₋₅ alkylbenzyl substituted in the phenyl moiety by R₅, R₆ and/or R₇,wherein:

R₅ and R₆, independently, are H; halogen, C₁₋₅ alkyl, C₂₋₅ alkenyl, C₂₋₅alkynyl, or C₁₋₅ alkoxy, (e.g., unsubstituted or halogenated), phenyl orphenoxy (e.g., unsubstituted or substituted), or NO₂; and

R₇ is H, C₁₋₅ alkyl or halogen.

In some embodiments, the compound represented by formula (XIV) is acompound represented by formula (XV)

wherein R₁, R₂, R₃, R₄, R₅, R₆, R₇, m and n are as defined for formula(XIV) herein, R₈ is H or C₁₋₅ alkyl, and Y is CH or N;

or a pharmaceutically acceptable salt, ester, or ether thereof.

In some embodiments, the compound represented by formula (XV) is acompound represented by formula (XVI)

wherein R₂ is hydrogen or optionally substituted alkyl, such asoptionally substituted lower alkyl (e.g., methyl, ethyl, n-propyl,iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl,n-hexyl, or the like); and

R₅ and R₆ are each independently hydrogen or a halogen atom, such aschloro;

or a pharmaceutically acceptable salt, ester, or ether thereof.

In some embodiments, the CYP51A1 inhibitor is2-(4-chlorophenyl)-3-cyclopropyl-1-(1H-1,2,4-triazol-1-yl)-butan-2-ol,2-(4-chlorophenyl)-3-cyclopropyl-3-methyl-1-(1H-1,2,4-triazol-1-yl)-butan-2-ol,2-(2,4-diclorophenyl)-3-cyclopropyl-1-(1H-1,2,4-triazol-1-yl)butan-2-ol, or2-(2,4-dichlorophenyl-3-cyclopropyl-3-methyl-1-(1H-1,2,4-triazol-1-yl)butan-2-ol.

Exemplary variants of cyproconazole useful in conjunction with thecompositions and methods described herein are described in U.S. Pat.Nos. 4,432,989 and 4,664,696, the disclosures of each of which areincorporated herein by reference in their entirety.

Voriconazole and Variants Thereof

In some embodiments, the CYP51A1 inhibitor is voriconazole or a variantthereof that retains CYP51A1 inhibitory activity, such as a compoundrepresented by formula (XVII)

wherein R is phenyl optionally substituted by 1 to 3 substituents eachindependently selected from halo and CF₃;

R¹ is C₁-C₄alkyl;

R₂ is H or C₁-C₄ alkyl; and

“Het”, which is attached to the adjacent carbon atom by a ring carbonatom, is selected from pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyland triazinyl. “Het” may be optionally substituted by C₁-C₄ alkyl, C₁-C₄alkoxy, halo, CF₃, CN, NO₂, NH₂, —NH(C₁-C₄ alkanoyl) or —NHCO₂(C₁-C₄alkyl);

or a pharmaceutically acceptable salt, ester, or ether thereof.

In some embodiments of formula (XVII), “Het” is selected from 2- and4-pyridinyl, pyridazinyl, 2- and 4-pyrimidinyl, pyrazinyl and triazinyl,and may be optionally substituted by C₁-C₄ alkyl, C₁-C₄ alkoxy, halo,CF₃, CN, NO₂, NH₂, —NH(C₁-C₄ alkanoyl) or —NHCO₂ (C₁-C₄ alkyl). In someembodiments, “Het” is pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl ortriazinyl, and may be optionally substituted by C₁-C₄ alkyl, C₁-C₄alkoxy, halo, CF₃, NO₂, NH₂ or —NH(C₁-C₄ alkanoyl).

In some embodiments of formula (XVII), R is a substituted phenyl moiety,such as 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-iodophenyl,2-trifluoromethylphenyl, 2,4-dichlorophenyl, 2,4-difluorophenyl,2-chloro-4-fluorophenyl, 2-fluoro-4-chlorophenyl, 2,5-difluorophenyl,2,4,6-trifluorophenyl, or 4-bromo-2,5-difluorophenyl. In someembodiments, R is a phenyl group substituted by from 1 to 3 halo(preferably F or Cl) substituents. In some embodiments, R is a phenylgroup substituted by from 1 or 2 halo (preferably F or Cl) substituents.In some embodiments, R is 2,4-difluorophenyl, 2,4-dichlorophenyl,2-fluorophenyl or 2-chlorophenyl.

In some embodiments, the CYP51A1 inhibitor is2-(2,4-difluorophenyl)-3-(pyridin-2-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol,2-(2,4-difluorophenyl)-3-(pyridin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol,or2-(2,4-difluorophenyl)-3-(pyrimidin-4-yl)-1H,1,2,4-triazol-1-yl)butan-2-ol.

In some embodiments, the CYP51A1 inhibitor is a compound represented byformula (XVIII)

wherein R is optionally substituted phenyl (e.g., substituted by from 1to 3 substituents each independently selected from halo, —CF₃ and—OCF₃);

R¹ is optionally substituted alkyl, such as optionally substituted loweralkyl (e.g., C₁-C₄ alkyl);

R₂ is H or optionally substituted alkyl, such as optionally substitutedlower alkyl (e.g., C₁-C₄ alkyl);

X is CH or N; and

Y is a halogen, such as F or Cl;

or a pharmaceutically acceptable salt, ester, or ether thereof.

Examples of R in formula (XVIII) are 2-fluorophenyl, 4-fluorophenyl,2-chlorophenyl, 4-chlorophenyl, 2-bromophenyl, 2-iodophenyl,2-trifluoromethylphenyl, 2,4-dichlorophenyl, 2,4-difluorophenyl,2-chloro-4-fluorophenyl, 2-fluoro-4-chlorophenyl, 2,5-difluorophenyl,2,4,6-trifluorophenyl, 4-bromo-2,5-difluorophenyl, and2-trifluoromethoxyphhenyl.

In some embodiments of formula (XVIII), the compound is represented byformula (XIX)

wherein R, R₁, R₂, X, and Y are as defined for formula (XVIII).

In some embodiments of formula (XVIII), the compound is represented byformula (XX)

wherein R, R₁, R₂, X, and Y are as defined for formula (XVIII).

In some embodiments of formula (XVIII), the compound is represented byformula (XXI)

wherein R, R₁, R₂, X, and Y are as defined for formula (XVIII).

In some embodiments, the CYP51A1 inhibitor is2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol,or a pharmaceutically acceptable salt, ester, or ether thereof. In someembodiments, the CYP51A1 inhibitor is(2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol,or a pharmaceutically acceptable salt, ester, or ether thereof.

Exemplary variants of voriconazole that may be used in conjunction withthe compositions and methods described herein are described, forexample, in U.S. Pat. No. 5,116,844, the disclosure of which isincorporated herein by reference in its entirety.

Fluconazole and Variants Thereof

In some embodiments, the CYP51A1 inhibitor is fluconazole or a variantthereof that retains CYP51A1 inhibitory activity, such as a compoundrepresented by formula (XXII)

wherein R₁ is an optionally substituted alkyl, cycloalkyl (e.g.cyclopentyl or cyclohexyl), aryl (e.g. phenyl) or arylalkyl (e.g.benzyl) group; and

Y₁ and Y₂ are each independently ═CH— or ═N—;

or a pharmaceutically acceptable salt, ester, or ether thereof.

In some embodiments of formula (XXII), R₁ is alkyl, cycloalkyl,optionally substituted aryl, or optionally substituted arylalkyl; and Y¹and Y² are either both ═CH— or both ═N—.

In some embodiments of formula (XXII), R₁ is phenyl or benzyl,optionally substituted with one or more of halogen, alkyl or haloalkyleach containing from 1 to 5 carbon atoms, alkoxy or haloalkoxy eachcontaining from 1 to 4 carbon atoms, nitro, cyano, hydroxy, alkylthiocontaining from 1 to 40 carbon atoms, vinyl, phenyl or phenoxy. In someembodiments, the alkyl moiety of the benzyl is unsubstituted, orsubstituted with alkyl containing from 1 to 4 carbon atoms, phenyl orchlorophenyl.

In some embodiments, the CYP51A1 inhibitor is selected from:

Exemplary variants of fluconazole that may be used in conjunction withthe compositions and methods described herein are described, forexample, in U.S. Pat. Nos. 4,416,682 and 4,404,216, the disclosures ofeach of which are incorporated herein by reference in their entirety.

Clotrimazole and Variants Thereof

In some embodiments, the CYP51A1 inhibitor is clotrimazole or a variantthereof that retains CYP51A1 inhibitory activity, such as a compoundrepresented by formula (XXIII)

wherein each of R₁, R₂, and R₃ is independently an aryl grouprepresented by the formula:

n is an integer of from 0 to 5 (e.g., an integer of from 0 to 2) andeach R′ is independently halogen or optionally substituted alkyl (e.g.,optionally substituted lower alkyl); and

each X is independently selected from hydrogen, optionally substitutedalkyl (e.g., optionally substituted lower alkyl), or optionallysubstituted aryl (e.g., optionally substituted phenyl);

or a pharmaceutically acceptable salt thereof. In some embodiments, thetotal number of carbon atoms in all X substituents is an integer of from0 to 15.

In some embodiments, the CYP51A1 inhibitor is a compound selected fromI-(tris(m-tert-butylphenyl)methyl) imidazole, 1-(tris(p-tert-butylphenylmethyl) imidazole, 1-(his(2,4-difiourophenyl)methyl)-2,4,5-trimethylimidazole,1-(tris(p-chlorophenyl)methyl)-2-methyl-4,5-diphenylimidazone,1-(tris(m-tolyl)methyl)-2-n-propylimidaz-ole, and1-trityl-2-methylimidazole.

In some embodiments, the CYP51A1 inhibitor is a compound represented byformula (XXIV)

wherein each of R, R₁, and R₂ is independently hydrogen, optionallysubstituted alkyl (e.g., optionally substituted lower alkyl), oroptionally substituted and optionally fused aryl (e.g., optionallysubstituted phenyl);

each of X, X′, and X′″ is independently hydrogen, halogen, optionallysubstituted alkyl (e.g., optionally substituted lower alkyl), oroptionally substituted and optionally fused aryl (e.g., optionallysubstituted phenyl); and

each of n, n′, and n″ is independently 1, 2, 3, 4, or 5 (e.g., 1, 2, or3).

In some embodiments of formula (XXIV), the compound is represented byformula (XXV)

wherein X, X′, X″′, n, n′, and n″ are as defined for formula (XXIV).

In some embodiments of formula (XXIV), the compound is represented byformula (XXVI)

wherein X, X′, X″′, n, n′, and n″ are as defined for formula (XXIV).

In some embodiments, the CYP51A1 inhibitor is1-(3,4-Dimethylphenyl-phenyl-2-pyridyl)-methyl-imidazole,1-(2,4-dimethylphenyl-phenyl-2-pyridyl)-methyl-imidazole,1-(2,6-dimethylphenyl-phenyl-2-pyridyl)-methyl-imidazole,1-(2,4-dimethylphenyl-phenyl-4-pyridyl)-methyl-imidazole,1-(3,4-dimethylphenyl-phenyl-4-pyridyl)-methyl-imidazole,1-(2,5-dimethylphenyl-phenyl-4-pyridyl)-methyl-imidazole,1-(2,3-dimethylphenyl-phenyl-2-pyridyl)-methyl-imidazole,1-(2,3-dimethylphenyl-phenyl-2-pyridyl)-methyl-imidazole,1-(2,3-dimethylphenyl-phenyl-2-pyridyl)-methyl-imidazole,1-(2,3-dimethylphenyl-phenyl-4-pyridyl)-methyl-imidazole,1-(3,4-dimethylphenyl-phenyl-4-pyridyl)-methyl-imidazole, or apharmaceutically acceptable salt thereof, such as the1,5-naphthalene-disulphonate salt thereof or the hydrochloride saltthereof.

Exemplary variants of clotrimazole that may be used in conjunction withthe compositions and methods described herein are described, forexample, in U.S. Pat. No. 3,321,366, the disclosure of which isincorporated herein by reference in its entirety.

Epoxiconazole and Variants Thereof

In some embodiments, the CYP51A1 inhibitor is epoxiconazole or a variantthereof that retains CYP51A1 inhibitory activity, such as a compoundrepresented by formula (XXVII)

wherein A and B are independently selected from optionally substitutedalkyl (e.g., optionally substituted lower alkyl, such as alkyl of 1 to 4carbon atoms), optionally substituted naphthyl, optionally substitutedbiphenyl, and optionally substituted phenyl, and Z is CH or N. In someembodiments, A and/or B is an optionally substituted phenyl group, suchas a phenyl group substituted by one or more of halogen, nitro, alkyl(e.g., of from 1 to 4 carbon atoms), alkoxy (e.g., of from 1 to 4 carbonatoms), haloalkyl (e.g., of from 1 to 4 carbon atoms), phenoxy, orphenylsulyfonyl.

In some embodiments, the CYP51A1 inhibitor is a compound represented byformula (XXVIII)

wherein R is optionally substituted aryl, such as phenyl, pyridyl,tetrahydropyranyl, norbornyl, C₃-C₁₂ cycloalkyl or C₅-C₈ cycloalkenyl,each of which may be unsubstituted or monosubstituted to trisubstitutedby halogen, nitro, phenoxy, alkyl, amino, alkoxy (e.g., of from 1 to 4carbon atoms), haloalkoxy (e.g., of from 1 to 4 carbon atoms), orhaloalkyl (e.g., of from 1 to 4 carbon atoms);

each X is independently fluorine, chlorine, bromine, or iodine; and

each n is independently an integer of from 1 to 5 (e.g., an integer offrom 1 to 3).

In some embodiments of formula (XXVIII), the compound is represented byformula (XXIX)

wherein R and X are as defined for formula (XXVIII).

In some embodiments of formula (XXVIII), the compound is represented byformula (XXX)

wherein R is as defined for formula (XXVIII).

Exemplary variants of epoxiconazole that may be used in conjunction withthe compositions and methods described herein are described, forexample, in U.S. Pat. Nos. 4,464,381 and 4,940,717, the disclosures ofeach of which are incorporated herein by reference in their entirety.

VNI, VNF, and Variants Thereof

In some embodiments, the CYP51A1 inhibitor is VNI, represented byformula (5), herein, or VNF, represented by formula (6), herein.

In some embodiments, the CYP51A1 inhibitor is a variant of VNI or VNFthat retains CYP51A1 inhibitory activity. For example, the CYP51A1inhibitor may be a compound represented by formula (XXXI)

wherein each of rings A and B are independently optionally substitutedand optionally fused aryl, heteroaryl, cycloalkyl, or heterocycloalkyl;

each X is independently halogen or optionally substituted alkyl (e.g.,optionally substituted lower alkyl); and

n is an integer of from 1 to 5 (e.g., an integer of from 1 to 3).

In some embodiments of formula (XXXI), the compound is represented byformula (XXXII)

wherein each X is independently halogen or optionally substituted alkyl(e.g., optionally substituted lower alkyl); and

each n is independently an integer of from 1 to 5 (e.g., an integer offrom 1 to 3).

In some embodiments of formula (XXXII), the compound is represented byformula (XXXIII)

wherein each X and n are as defined for formula (XXXII).

In some embodiments, the CYP51A1 inhibitor is a compound represented byformula (XXXIV)

wherein each X is independently halogen or optionally substituted alkyl(e.g., optionally substituted lower alkyl); and

each n is independently an integer of from 1 to 5 (e.g., an integer offrom 1 to 3).

In some embodiments of formula (XXXIV), the compound is represented byformula (XXXV)

wherein each X and n are as defined for formula (XXXIV).

Ketoconazole and Variants Thereof

In some embodiments, the CYP51A1 inhibitor is ketoconazole or a variantthereof that retains CYP51A1 inhibitory activity, such as a compoundrepresented by formula(XXXVI)

wherein Q is selected from the group consisting of CH and N;

Ar is an optionally substituted, optionally fused aryl group, such as anoptionally fused, optionally substituted phenyl group, for example, aphenyl group having from 1 to 3 substituents, such as from 1 to 3substituents independently selected from the group consisting of halo,lower alkyl and lower alkyloxy;

A is selected from the group consisting of:

-   -   (a) an isothiocyanato group —N═C═S;    -   (b) an amino group of the formula

-   -   wherein R₁ and R₂ are each independently selected from the group        consisting of hydrogen and lower alkyl;    -   (c) a group of the formula

-   -   wherein X is selected from the group consisting of O and S, Y is        selected from the group consisting of O and NH, m is the integer        0 or 1, and R₃ is selected from the group consisting of        hydrogen, lower alkyl, mono- and dihalo-(lower alkyl), phenyl        and substituted phenyl, said substituted phenyl having from 1 to        2 substituents independently selected from the group consisting        of halo, lower alkyl and lower alkyloxy, optionally provided        that:        -   i) when said X is S, then said Y is NH and said m is 1; and        -   ii) when said Y is O and said m is 1, then said R₃ is other            than hydrogen; and    -   (d) a group of the formula

-   -   wherein Z is selected from the group consisting of a direct        bond, CH₂, O and N—R₄, wherein R₄ is selected from the group        consisting of hydrogen, lower alkyl, hydroxy-(lower alkyl),        (lower alkyloxy)-lower alkyl, lower alkanoyl, lower        alkylsulfonyl, phenylmethylsulfonyl, lower alkyloxycarbonyl,        lower alkyloxycarbonylmethyl, phenoxycarbonyl, aminocarbonyl,        mono- and di(lower alkyl)aminocarbonyl, aminocarbonylmethyl,        (lower alkyl)aminocarbonylmethyl, (lower        alkyl)aminothioxomethyl, (lower alkylthio)thioxomethyl, phenyl,        phenylmethyl, benzoyl and substituted benzoyl, said substituted        benzoyl being benzoyl having from 1 to 2 substituents        independently selected from the group consisting of halo, lower        alkyl and lower alkyloxy; and R is selected from the group        consisting of hydrogen and nitro, optionally provided that when        said R is nitro, then said A is amino.

In some embodiments, the CYP51A1 inhibitor is a compound represented byformula (XXXVII)

wherein Q is selected from the group consisting of N and CH;

Ar is selected from the group consisting of phenyl, thienyl, halothienyland substituted phenyl, the substituted phenyl having from 1 to 3substituents each independently selected from the group consisting ofhalo, lower alkyl, lower alkyloxy and trifluoromethyl; and the group Yis selected from the group consisting of:

-   -   a group of the formula —SO₂R₁, wherein R₁ is selected from the        group consisting of trifluoromethyl and aryl;    -   a group of formula -alk-R₂, wherein alk is selected from the        group consisting of lower alkylene and lower alkenylene and R₂        is selected from the group consisting of cyano, amino, mono- and        di(lower alkyl)amino, arylamino, mono- and di(aryllower        alkyl)amino, 1-pyrrolidinyl, 1-morpholinyl, 1-piperidinyl,        aryloxy and aryl, provided that alk is other than methylene when        R₂ is phenyl;    -   a group of formula

-   -   wherein n is an integer of from 0 to 6 inclusive, X is O or S        and R₃ is selected from the group consisting of hydrogen, mono-,        di- and trihalolower alkyl, amino, mono- and di(lower        alkyl)amino, arylamino, mono- and di(aryllower alkyl)amino,        amino lower alkyl, mono- and di(lower alkyl)amino lower alkyl,        (1-pyrrolidinyl)lower alkyl, (1-morpholinyl)lower alkyl,        (1-piperidinyl)lower alkyl, aryl, aryllower alkyl, aryllower        alkenyl and lower alkyloxycarbonyl lower alkyloxy, optionally        provided that:        -   (i) said n is other than 0 or 1 when said R₃ is amino or            lower alkylamino; and        -   (ii) said n is other than 0 when said R₃ is di(lower            alkyl)amino or aryl; and    -   a group of formula

-   -   wherein m is an integer of from 1 to 6 inclusive, A is O or NH,        X is O or S and R₄ is selected from the group consisting of        hydrogen, lower alkyl, lower alkyloxy, aryl, aryloxy, aryllower        alkyl, amino, mono- and di(lower alkyl)amino, arylamino, mono-        and di(aryllower alkyl)amino, 1-pyrrolidinyl, 1-morpholinyl and        1-piperidinyl;        wherein said aryl, as used in the foregoing definitions, is        selected from the group consisting of phenyl, substituted        phenyl, thienyl, halothienyl, lower alkylthienyl and pyridinyl,        said substituted phenyl having from 1 to 3 substituents each        independently selected from the group consisting of lower alkyl,        lower alkyloxy, halo, amino, mono- and di(lower alkyl)amino,        lower alkylcarbonylamino, nitro and trifluoromethyl.

Exemplary variants of ketoconazole that may be used in conjunction withthe compositions and methods described herein are described, forexample, in U.S. Pat. Nos. 4,144,346 and 4,503,055, the disclosures ofeach of which are incorporated herein by reference in their entirety.

Prochloraz and Variants Thereof

In some embodiments, the CYP51A1 inhibitor is prochloraz, represented byformula (7), below.

In some embodiments, the CYP51A1 inhibitor is a variant of prochlorazthat retains CYP51A1 inhibitory activity, such as a compound representedby formula (XXXVIII)

wherein X is oxygen or sulfur, R₁ is optionally substituted alkyl,alkenyl, alkynyl, cycloalkyl, phenyl, phenylalkyl, phenylalkenyl,phenoxyalkyl or phenylthioalkyl and R₂ is optionally substituted phenyl,phenylalkyl, phenylalkenyl, phenoxyalkyl or phenylthioalkyl, providedthat when R₁ is methyl or phenyl R₂ is substituted phenyl or optionallysubstituted phenylalkyl, phenylalkenyl, phenoxyalkyl or phenylthioalkyl.

In some embodiments of formula (XXXVIII), X is selected from the groupconsisting of oxygen and sulfur, R₁ is selected from the groupconsisting of alkyl of 1 to 10 carbon atoms, alkenyl of 3 or 4 carbonatoms, alkynyl of 3 to 5 carbon atoms, cycloalkyl of 3 to 10 carbonatoms, optionally substituted phenyl, phenylalkyl, of the formulaPh(CH₂)_(n) where n is 1 to 5, phenylalkenyl of 9 to 11 carbon atoms,phenoxyalkyl of the formula PhO(CH₂)_(n) where n is 2 to 5 andphenylthioalkyl of the formula PhS(CH₂)_(n) where n is 2 to 5, whereinthe substituted phenyl nucleus has at least one substituent selectedfrom the group consisting of halo, alkoxy of 1 or 2 carbon atoms, alkylof 1 to 4 carbon atoms, trihalomethyl, cyano, methylthio, nitro andmethylsulphonyl, and R₂ is selected from the group consisting ofoptionally substituted phenylalkyl, of the formula Ph(CH₂)_(n) where nis 1 to 5, phenylalkenyl of 9 to 11 carbon atoms, phenoxyalkyl of theformula PhO(CH₂)_(n) where n is 2 to 5 and phenylthioalkyl of theformula PhS(CH₂)_(n) where n is 2 to 5, wherein the substituted phenylnucleus has at least one substituent selected from the group consistingof halo, alkoxy of 1 or 2 carbon atoms, alkyl of 1 to 4 carbon atoms,trihalomethyl, cyano, methylthio, nitro and methylsulphonyl.

Exemplary variants of prochloraz that may be used in conjunction withthe compositions and methods described herein are described, forexample, in U.S. Pat. No. 4,080,462, the disclosure of which isincorporated herein by reference in its entirety.

Propiconazole and Variants Thereof

In some embodiments, the CYP51A1 inhibitor is propiconazole, representedby formula (8), below.

In some embodiments, the CYP51A1 inhibitor is a variant of propiconazolethat retains CYP51A1 inhibitory activity, such as a compound representedby formula (XXXIX)

wherein Z is an alkylene selected from the group consisting of —CH₂CH₂—,—CH₂—CH₂CH₂—, —CH(CH₃)CH(CH₃)—, and —CH₂CH(alkyl)-, wherein the alkylhas from 1 to about 10 carbon atoms; and

Ar is an optionally fused, optionally substituted aryl group, such as anoptionally fused, optionally substituted phenyl, thienyl, naphthyl, orfluorenyl, for example, phenyl, thienyl, halothienyl, naphthyl andfluorenyl, each optionally containing one or more (e.g., from 1 to 3)substituents selected independently from the group consisting of halo,lower alkyl, lower alkyloxy, cyano, and nitro.

Exemplary variants of propiconazole that may be used in conjunction withthe compositions and methods described herein are described, forexample, in U.S. Pat. No. 4,079,062, the disclosure of which isincorporated herein by reference in its entirety.

Prothioconazole, Prothioconazole-desthio, and Variants Thereof

In some embodiments, the CYP51A1 inhibitor is prothioconazole,represented by formula (8), below.

In some embodiments, the CYP51A1 inhibitor is prothioconazole-desthio,represented by formula (9), below.

In some embodiments, the CYP51A1 inhibitor is a variant ofprothioconazole or prothioconazole-desthio that retains CYP51A1inhibitory activity, such as a compound represented by formula (XL)

wherein R₁ and R₂ are each independently selected from optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted cycloalkyl, optionally substituted aralkyl, optionallysubstituted aralkenyl, optionally substituted aroxyalkyl, optionallysubstituted aryl, and optionally substituted heteroaryl; and

X is —SH, —SR₃, —SO—R₃, —SO₂—R₃, or —SO₃H, wherein R₃ is alkyl which isoptionally substituted by one or more halogen moieties (e.g., fluorineand/or chlorine), alkenyl which is optionally substituted by one or morehalogen moieties (e.g., fluorine and/or chlorine), optionallysubstituted aralkyl or optionally substituted aryl.

Exemplary variants of prothioconazole and prothioconazole-desthio thatmay be used in conjunction with the compositions and methods describedherein are described, for example, in U.S. Pat. No. 5,789,430, thedisclosure of which is incorporated herein by reference in its entirety.

Tebuconazole and Variants Thereof

In some embodiments, the CYP51A1 inhibitor is tebuconazole, representedby formula (10), below.

In some embodiments, the CYP51A1 inhibitor is a variant of tebuconazolethat retains CYP51A1 inhibitory activity, such as a compound representedby formula (XLI)

wherein R₁ is —CH═CH—X, —C≡C—X, or —CH₂—CH₂—X, wherein X is hydrogen,alkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl or optionally substitutedaryl, aralkyl, aryloxy alkyl, or heterocycle;

R₂ is alkyl, cycloalkyl (e.g. cyclopropyl, cyclopentyl, or cyclohexyl)or optionally substituted aryl;

Z is Cl, CN, or OR₃, wherein R₃ is hydrogen, acetyl, alkyl, alkenyl oraralkyl; and

Y is ═N— or ═CH—,

or a pharmaceutically acceptable salt, ester, or ether thereof.

Exemplary variants of tebuconazole that may be used in conjunction withthe compositions and methods described herein are described, forexample, in U.S. Pat. No. 4,507,140, the disclosure of which isincorporated herein by reference in its entirety.

Triadimenol and Variants Thereof

In some embodiments, the CYP51A1 inhibitor is triadimenol, representedby formula (11), below.

In some embodiments, the CYP51A1 inhibitor is a variant of triadimenolthat retains CYP51A1 inhibitory activity, such as a compound representedby formula (XLII)

wherein X₁ is hydrogen or an alkyl group,

X₂ is hydrogen or an alkyl group,

R₁ is an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl or optionallysubstituted aryl or aralkyl group,

R₂ is hydrogen or an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenylor optionally substituted aryl or aralkyl group,

R₃ is hydrogen or an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenylor optionally substituted aryl or aralkyl group, and

Y is a keto group or a functional keto derivative.

or a pharmaceutically acceptable salt, ester, or ether thereof.

Exemplary variants of triadimenol that may be used in conjunction withthe compositions and methods described herein are described, forexample, in U.S. Pat. No. 3,912,752, the disclosure of which isincorporated herein by reference in its entirety.

Azalanstat and Variants Thereof

In some embodiments, the CYP51A1 inhibitor is azalanstat, represented byformula (12), below.

In some embodiments, the CYP51A1 inhibitor is a variant of azalanstatthat retains CYP51A1 inhibitory activity, such as a compound representedby formula (XLIII)

wherein n is 2 or 3;

p is 0, 1 or 2;

q is 0, 1 or 2;

X is oxygen or S(O)_(t) wherein t is 0, 1, or 2;

each R₁ is independently halo, lower alkyl, lower alkoxy, ortrifluoromethyl;

each R₂ is independently halo or lower alkyl;

R₃ is nitro or —N(R₅)R₆ where

R₅ is hydrogen or lower alkyl;

R₆ is hydrogen, lower alkyl, lower alkylsulfonyl or —C(Y)R₇ where Y isoxygen or sulfur and R₇ is hydrogen, lower alkyl, lower alkoxy or—N(R₈)R₉ where R₈ is hydrogen or lower alkyl and R₉ is hydrogen, loweralkyl or lower alkoxycarbonyl; or

R₅ and R₆ together with N is pyrrolidino, piperidino, morpholino,thiomorpholino or piperazino, wherein the piperazino is optionallysubstituted at the 4-position by —C(O)R₁₀ where R₁₀ is hydrogen, loweralkyl, lower alkoxy or amino; and

R₄ is hydrogen or optionally substituted lower alkyl;

or a pharmaceutically acceptable salt, ester, or ether thereof.

In some embodiments of formula (XLIII), the compound is represented byformula (XLIV)

wherein R₁, R₂, R₃, R₄, X, n, p, and q are as defined for formula(XLIII).

In some embodiments of formula (XLIII), the compound is represented byformula (XLV)

wherein R₁, R₂, R₃, R₄, X, n, p, and q are as defined for formula(XLIII).

In some embodiments of formula (XLIII), the compound is represented byformula (XLVI)

wherein R₁, R₂, R₃, R₄, X, n, p, and q are as defined for formula(XLIII).

In some embodiments of formula (XLIII), the compound is represented byformula (XLVII)

wherein R₁, R₂, R₃, R₄, X, n, p, and q are as defined for formula(XLIII).

In some embodiments of formula (XLIII), the compound is represented byformula (XLVIII)

wherein R₁, R₂, R₃, R₄, X, n, p, and q are as defined for formula(XLIII).

Exemplary variants of azalanstat that may be used in conjunction withthe compositions and methods described herein are described, forexample, in U.S. Pat. No. 5,158,949, the disclosure of which isincorporated herein by reference in its entirety.

Antibody Inhibitors of CYP51A1

CYP51A1 inhibitors useful in conjunction with the compositions andmethods described herein include antibodies and antigen-bindingfragments thereof, such as those that specifically bind to CYP51A1and/or inhibit CYP51A1 catalytic activity. In some embodiments, theantibody or antigen-binding fragment thereof is a monoclonal antibody orantigen-binding fragment thereof, a polyclonal antibody orantigen-binding fragment thereof, a humanized antibody orantigen-binding fragment thereof, a bispecific antibody orantigen-binding fragment thereof, a dual-variable immunoglobulin domain,a single-chain Fv molecule (scFv), a diabody, a triabody, a nanobody, anantibody-like protein scaffold, a Fv fragment, a Fab fragment, a F(ab′)₂molecule, and a tandem di-scFv. In some embodiments, the antibody has anisotype selected from IgG, IgA, IgM, IgD, and IgE.

Interfering RNA Inhibitors of CYP51A1

CYP51A1 inhibitors useful in conjunction with the compositions andmethods described herein include interfering RNA molecules, such asshort interfering RNA (siRNA) molecules, micro RNA (miRNA) molecules, orshort hairpin RNA (shRNA) molecules. The interfering RNA may suppressexpression of a CYP51A1 mRNA transcript, for example, by way of (i)annealing to a CYP51A1 mRNA or pre-mRNA transcript, thereby forming anucleic acid duplex; and (ii) promoting nuclease-mediated degradation ofthe CYP51A1 mRNA or pre-mRNA transcript and/or (iii) slowing,inhibiting, or preventing the translation of a CP51A1 mRNA transcript,such as by sterically precluding the formation of a functionalribosome-RNA transcript complex or otherwise attenuating formation of afunctional protein product from the target RNA transcript.

In some embodiments, the interfering RNA molecule, such as the siRNA,miRNA, or shRNA, contains an antisense portion that anneals to a segmentof a CYP51A1 RNA transcript (e.g., mRNA or pre-mRNA transcript), such asa portion that anneals to a segment of a CYP51A1 RNA transcript having anucleic acid sequence that is at least 85% identical to the nucleic acidsequence of SEQ ID NO: 2 (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%,93%, 94%, 95%<96%, 97%, 98%, 99%, 99.9%, or 100% identical to thenucleic acid sequence of SEQ ID NO: 2).

In some embodiments, the interfering RNA molecule, such as the siRNA,miRNA, or shRNA, contains a sense portion having at least 85% sequenceidentity to the nucleic acid sequence of a segment of SEQ ID NO: 2(e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%<96%, 97%,98%, 99%, 99.9%, or 100% identical to the nucleic acid sequence of asegment of SEQ ID NO: 2).

Interfering RNAs as described herein may be provided to a patient, suchas a human patient having a neurological disorder described herein, inthe form of, for example, a single- or double-stranded oligonucleotide,or in the form of a vector (e.g., a viral vector) containing a transgeneencoding the interfering RNA. Exemplary interfering RNA platforms aredescribed, for example, in Lam et al., Molecular Therapy -Nucleic Acids4:e252 (2015); Rao et al., Advanced Drug Delivery Reviews 61:746-769(2009); and Borel et al., Molecular Therapy 22:692-701 (2014), thedisclosures of each of which are incorporated herein by reference intheir entirety.

Methods of Treatment

Suppression of CYP51A1 Activity and TDP-43 Aggregation to TreatNeurological Disorders

Using the compositions and methods described herein, a patient sufferingfrom a neurological disorder may be administered a CYP51A1 inhibitor,such as a small molecule, antibody, antigen-binding fragment thereof, orinterfering RNA molecule described herein, so as to treat the disorderand/or to suppress one or more symptoms associated with the disorder.Exemplary neurological disorders that may be treated using thecompositions and methods described herein are, without limitation,amyotrophic lateral sclerosis, frontotemporal degeneration, Alzheimer'sdisease, Parkinson's disease, dementia with Lewy Bodies, corticobasaldegeneration, progressive supranuclear palsy, dementia parkinsonism ALScomplex of Guam, Huntington's disease, IBMPFD, sporadic inclusion bodymyositis, myofibrillar myopathy, dementia pugilistica, chronic traumaticencephalopathy, Alexander disease, and hereditary inclusion bodymyopathy, as well as neuromuscular diseases such as congenitalmyasthenic syndrome, congenital myopathy, cramp fasciculation syndrome,Duchenne muscular dystrophy, glycogen storage disease type II,hereditary spastic paraplegia, inclusion body myositis, Isaac'sSyndrome, Kearns-Sayre syndrome, Lambert-Eaton myasthenic syndrome,mitochondrial myopathy, muscular dystrophy, myasthenia gravis, myotonicdystrophy, peripheral neuropathy, spinal and bulbar muscular atrophy,spinal muscular atrophy, Stiff person syndrome, Troyer syndrome, andGuillain-Barré syndrome.

The present disclosure is based, in part, on the discovery that CYP51A1inhibitors, such as the agents described herein, are capable ofattenuating TDP-43 aggregation in vivo. TDP-43-promoted aggregation andtoxicity have been associated with various neurological diseases. Thediscovery that CYP51A1 inhibitors modulate TDP-43 aggregation providesan important therapeutic benefit. Using a CYP51A1 inhibitor, such as aCYP51A1 inhibitor described herein, a patient suffering from aneurological disorder or at risk of developing such a condition may betreated in a manner that remedies an underlying molecular etiology ofthe disease. Without being limited by mechanism, the compositions andmethods described herein can be used to treat or prevent suchneurological conditions, for example, by suppressing the TDP-43aggregation that promotes pathology.

Additionally, the compositions and methods described herein provide thebeneficial feature of enabling the identification and treatment ofpatients that are likely to respond to CYP51A1 inhibitor therapy. Forexample, in some embodiments, a patient (e.g., a human patient sufferingfrom or at risk of developing a neurological disease described herein,such as amyotrophic lateral sclerosis) is administered a CYP51A1inhibitor if the patient is identified as likely to respond to this formof treatment. Patients may be identified as such on the basis, forexample, of susceptibility to TDP-43 aggregation. In some embodiments,the patient is identified is likely to respond to CYP51A1 inhibitortreatment based on the isoform of TDP-43 expressed by the patient. Forexample, patients expressing TDP-43 isoforms having a mutation selectedfrom Q331K, M337V, Q343R, N345K, R361S, and N390D, among others, aremore likely to develop TDP-43-promoted aggregation and toxicity relativeto patients that do not express such isoforms of TDP-43. Using thecompositions and methods described herein, a patient may be identifiedas likely to respond to CYP51A1 inhibitor therapy on the basis ofexpressing such an isoform of TDP-43, and may subsequently beadministered a CYP51A1 inhibitor so as to treat or prevent one or moreneurological disorders, such as one or more of the neurologicaldisorders described herein.

Assessing Patient Response

A variety of methods known in the art and described herein can be usedto determine whether a patient having a neurological disorder (e.g., apatient at risk of developing TDP-43 aggregation, such as a patientexpressing a mutant form of TDP-43 having a mutation associated withelevated TDP-43 aggregation and toxicity, for example, a mutationselected from Q331K, M337V, Q343R, N345K, R361S, and N390D) isresponding favorably to CYP51A1 inhibition. For example, successfultreatment of a patient having a neurological disease, such asamyotrophic lateral sclerosis, with a CYP51A1 inhibitor described hereinmay be signaled by:

(i) an improvement in condition as assessed using the amyotrophiclateral sclerosis functional rating scale (ALSFRS) or the revised ALSFRS(ALSFRS-R), such as an improvement in the patient's ALSFRS or ALSFRS-Rscore within one or more days, weeks, or months following administrationof the CYP51A1 inhibitor (e.g., an improvement in the patient's ALSFRSor ALSFRS-R score within from about 1 day to about 48 weeks (e.g.,within from about 2 days to about 36 weeks, from about 4 weeks to about24 weeks, from about 8 weeks to about 20 weeks, or from about 12 weeksto about 16 weeks), or more, following the initial administration of theCYP51A1 inhibitor to the patient, such as within 1 day, 2 days, 3 days,4 days, 5 days, 6 days, 7 days, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48weeks, or more, following the initial administration of the CYP51A1inhibitor to the patient);

(ii) an increase in slow vital capacity, such as an increase in thepatient's slow vital capacity within one or more days, weeks, or monthsfollowing administration of the CYP51A1 inhibitor (e.g., an increase inthe patient's slow vital capacity within from about 1 day to about 48weeks (e.g., within from about 2 days to about 36 weeks, from about 4weeks to about 24 weeks, from about 8 weeks to about 20 weeks, or fromabout 12 weeks to about 16 weeks), or more, following the initialadministration of the CYP51A1 inhibitor to the patient, such as within 1day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 2 weeks, 3 weeks, 4weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks,12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47weeks, 48 weeks, or more, following the initial administration of theCYP51A1 inhibitor to the patient);

(iii) a reduction in decremental responses exhibited by the patient uponrepetitive nerve stimulation, such as a reduction that is observedwithin one or more days, weeks, or months following administration ofthe CYP51A1 inhibitor (e.g., a reduction that is observed within fromabout 1 day to about 48 weeks (e.g., within from about 2 days to about36 weeks, from about 4 weeks to about 24 weeks, from about 8 weeks toabout 20 weeks, or from about 12 weeks to about 16 weeks), or more,following the initial administration of the CYP51A1 inhibitor to thepatient, such as within 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7days, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44weeks, 45 weeks, 46 weeks, 47 weeks, 48 weeks, or more, following theinitial administration of the CYP51A1 inhibitor to the patient);

(iv) an improvement in muscle strength, as assessed, for example, by wayof the Medical Research Council muscle testing scale (as described,e.g., in Jagtap et al., Ann. Indian. Acad. Neurol. 17:336-339 (2014),the disclosure of which is incorporated herein by reference as itpertains to measuring patient response to neurological diseasetreatment), such as an improvement that is observed within one or moredays, weeks, or months following administration of the CYP51A1 inhibitor(e.g., an improvement that is observed within from about 1 day to about48 weeks (e.g., within from about 2 days to about 36 weeks, from about 4weeks to about 24 weeks, from about 8 weeks to about 20 weeks, or fromabout 12 weeks to about 16 weeks), or more, following the initialadministration of the CYP51A1 inhibitor to the patient, such as within 1day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 2 weeks, 3 weeks, 4weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks,12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47weeks, 48 weeks, or more, following the initial administration of theCYP51A1 inhibitor to the patient);

(v) an improvement in quality of life, as assessed, for example, usingthe amyotrophic lateral sclerosis-specific quality of life (ALS-specificQOL) questionnaire, such as an improvement in the patient's quality oflife that is observed within one or more days, weeks, or monthsfollowing administration of the CYP51A1 inhibitor (e.g., an improvementin the subject's quality of life that is observed within from about 1day to about 48 weeks (e.g., within from about 2 days to about 36 weeks,from about 4 weeks to about 24 weeks, from about 8 weeks to about 20weeks, or from about 12 weeks to about 16 weeks), or more, following theinitial administration of the CYP51A1 inhibitor to the patient, such aswithin 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 2 weeks, 3weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks,11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46weeks, 47 weeks, 48 weeks, or more, following the initial administrationof the CYP51A1 inhibitor to the patient);

(vi) a decrease in the frequency and/or severity of muscle cramps, suchas a decrease in cramp frequency and/or severity within one or moredays, weeks, or months following administration of the CYP51A1 inhibitor(e.g., a decrease in cramp frequency and/or severity within from about 1day to about 48 weeks (e.g., within from about 2 days to about 36 weeks,from about 4 weeks to about 24 weeks, from about 8 weeks to about 20weeks, or from about 12 weeks to about 16 weeks), or more, following theinitial administration of the CYP51A1 inhibitor to the patient, such aswithin 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 2 weeks, 3weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks,11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46weeks, 47 weeks, 48 weeks, or more, following the initial administrationof the CYP51A1 inhibitor to the patient); and/or

(vii) a decrease in TDP-43 aggregation, such as a decrease in TDP-43aggregation within one or more days, weeks, or months followingadministration of the CYP51A1 inhibitor (e.g., a decrease in TDP-43aggregation within from about 1 day to about 48 weeks (e.g., within fromabout 2 days to about 36 weeks, from about 4 weeks to about 24 weeks,from about 8 weeks to about 20 weeks, or from about 12 weeks to about 16weeks), or more, following the initial administration of the CYP51A1inhibitor to the patient, such as within 1 day, 2 days, 3 days, 4 days,5 days, 6 days, 7 days, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 weeks, ormore, following the initial administration of the CYP51A1 inhibitor tothe patient.

Routes of Administration and Dosing

CYP51A1 inhibitors (e.g., inhibitory small molecules, antibodies,antigen-binding fragments thereof, and interfering RNA molecules)described herein may be administered to a patient (e.g., a human patienthaving one or more neurological disorders described herein) by a varietyof routes. Exemplary routes of administration are oral, transdermal,subcutaneous, intranasal, intravenous, intramuscular, intraocular,parenteral, topical, intrathecal, and intracerebroventricularadministration. The most suitable route for administration in any givencase will depend on the particular agent being administered, thepatient, pharmaceutical formulation methods, administration methods(e.g., administration kinetics), the patient's age, body weight, sex,severity of the diseases being treated, the patient's diet, and thepatient's excretion rate, among other factors.

Therapeutic compositions can be administered with medical devices knownin the art. For example, therapeutic compositions described herein canbe administered with a needleless hypodermic injection device, such asthe devices disclosed in U.S. Pat. Nos. 5,399,163; 5,383,851; 5,312,335;5,064,413; 4,941,880; 4,790,824; or 4,596,556. Examples of implants andmodules useful in conjunction with the routes of administrationdescribed herein are those described in U.S. Pat. No. 4,487,603, whichdiscloses an implantable micro-infusion pump for dispensing medicationat a controlled rate; U.S. Pat. No. 4,486,194, which discloses atherapeutic device for administering medicaments through the skin; U.S.Pat. No. 4,447,233, which discloses a medication infusion pump fordelivering medication at a precise infusion rate; U.S. Pat. No.4,447,224, which discloses a variable flow implantable infusionapparatus for continuous drug delivery; U.S. Pat. No. 4,439,196, whichdiscloses an osmotic drug delivery system having multi-chambercompartments; and U.S. Pat. No. 4,475,196, which discloses an osmoticdrug delivery system. These patents are incorporated herein by referenceas they pertain to devices suitable for administration of a therapeuticagent to a patient (e.g., a human patient). Various other such implants,delivery systems, and modules are known to those skilled in the art.

Pharmaceutical Compositions

The CYP51A1 inhibitors (e.g., small molecules, antibodies,antigen-binding fragments thereof, and interfering RNA moleculesdescribed herein) suitable for use with the compositions and methodsdescribed herein can be formulated into pharmaceutical compositions foradministration to a patient, such as a human patient exhibiting or atrisk of developing TDP-43 aggregation, in a biologically compatible formsuitable for administration in vivo. A pharmaceutical compositioncontaining, for example, a CYP51A1 inhibitor described herein, such asLEK-935, CP-320626, itraconazole, posaconazole, cyproconazole,voriconazole, fluconazole, clotrimazol, fenticonazole, epoxiconazole,ketoconazole, ravuconazole, isavuconazole, holothurin A, theasaponin,capsicosine, betulafolientriol, prochloraz, propiconazole,prothioconazole, prothioconazole-desthio, tebuconazole, triadimenol,azalanstat, or a variant thereof, or an antibody, antigen-bindingfragment thereof, or interfering RNA molecule described herein, mayadditionally contain a suitable diluent, carrier, or excipient. CYP51A1inhibitors can be formulated for administration to a subject, forexample, by way of any one or more of the routes of administrationdescribed above. Under ordinary conditions of storage and use, apharmaceutical composition may contain a preservative, e.g., to preventthe growth of microorganisms. Procedures and ingredients for theselection and preparation of suitable formulations are described, forexample, in Remington: The Science and Practice of Pharmacy (2012,22^(nd) ed.) and in The United States Pharmacopeia: The NationalFormulary (2015, USP 38 NF 33).

Pharmaceutical compositions may include sterile aqueous solutions,dispersions, or powders, e.g., for the extemporaneous preparation ofsterile solutions or dispersions. In all cases the form may besterilized using techniques known in the art and may be fluidized to theextent that may be easily administered to a patient in need oftreatment.

A pharmaceutical composition may be administered to a patient, e.g., ahuman patient, alone or in combination with one or more pharmaceuticallyacceptable carriers, e.g., as described herein, the proportion of whichmay be determined by the solubility of the compound, the chemical natureof the compound, and/or the chosen route of administration, among otherfactors.

EXAMPLES

The following examples are put forth so as to provide those of ordinaryskill in the art with a description of how the compositions and methodsdescribed herein may be used, made, and evaluated, and are intended tobe purely exemplary of the invention and are not intended to limit thescope of what the inventors regards as their invention.

Example 1. Inhibition of CYP51A1 Modulates TDP-43 AggregationIntroduction

Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease,is an aggressive, debilitating disease in which affected patientssuccumb within two to five years after diagnosis. ALS presents withheterogeneous clinical features but has a common underlying pathology ofmotor neuron loss that limits the central nervous system's ability toeffectively regulate voluntary and involuntary muscle activity.Additionally, without neuronal trophic support muscles being to atrophy,further exacerbating motor deterioration. Cellular and tissuedegeneration results in motor impairment such as fasciculations andweakening in the arms, legs and neck, difficulty swallowing, slurredspeech and ultimately failure of the diaphragm muscles that controlbreathing.

At the cellular level, 97% of all ALS cases have the common pathologicalfeature of misfolded and aggregated TAR-DNA binding protein (TDP)-43 inspinal motor neuron inclusions. TDP-43 is a DNA/RNA binding proteininvolved in RNA splicing and is typically localized to the nucleus butcan be translocated to the cytoplasm under conditions of cell stress.Nuclear clearing and cytoplasmic accumulation of misfolded andaggregated TDP-43 are hallmarks of degenerating motor neurons in ALS,but it remains unclear if mechanism of toxicity is due toaggregation-dependent loss of TDP-43 function or if the aggregatesacquire toxic gain of function. Aggregates of TDP-43 accumulate indiscrete cellular domains known as stress granules, which are alsoenriched with translationally inactive mRNAs. Stress granules areobserved in multiple cellular types and are thought to be directlyrelated to TDP-43-dependent toxicity in ALS and FTD. Dysfunction inDNA/RNA binding protein activity plays a crucial role in susceptiblemotor neurons in ALS, as familial cases have also been traced tomutations in the protein Fused in Sarcoma (FUS), a DNA/RNA bindingprotein that recently has been shown to be involved in gene silencing.Preclinical studies suggest that FUS mutations promote a toxic gain offunction that may be causative in motor neuron degeneration.

Mutations in the TDP-43 gene (TARDBP) have also been causally linked tofamilial forms of ALS. A common TDP-43 mutation is known as Q331K, inwhich glutamine (Q) 331 has been mutated to a lysine (K). This mutationresults in a TDP-43 protein that is more aggregation prone and exhibitsenhanced toxicity. A recent study has also demonstrated that the Q331Kmutation can confer a toxic gain of function in a TDP-43 knock-in mouse,which exhibits cognitive deficits and histological abnormalities similarto that which occurs in frontotemporal dementia (FTD). FTD refers to agroup of degenerative disorders that are characterized by atrophy in thefrontal and temporal cortices due to progressive neuron loss. Due to thefunctional nature of the brain regions impacted in FTD, the most commonsymptoms involve noticeable alterations in personality, behavior andlinguistic ability and can also present with loss of speech. Thepathological basis of FTD appears to be multifactorial involvingmutations in genes such as C9orf72, progranulin (GRN) and MAPT, butintracellular inclusions of aggregated TDP-43, FUS and tau have beenobserved. Although ALS and FTD may have different genetic and moleculartriggers and occur in different cell types, similar protein misfoldingand degenerative mechanisms may operate in multiple diseases.

The toxic gain of function features of TDP-43 can be faithfullyrecapitulated in the simple model organism, budding yeast, where theprotein also localizes to stress granules. Human disease mutations inTDP-43 enhance toxicity and yeast genetic screens have revealed keyconnections that are conserved to humans. The yeast model thus providesa robust cell-based screening platform for small molecules capable ofameliorating toxicity. To validate compounds from such phenotypicscreens, it is imperative to test compounds in a mammalian neuronalcontext. In an effort to develop TDP-43-related mammalian models ofneuron loss that occurs in ALS and FTD, primary cultures of rat corticalneurons were transfected with human wild type or Q331K mutant TDP-43.These cells were compared to cells which received an empty expressionvector control. Validation studies have demonstrated that cellsexpressing either wild type or Q331K TDP-43 have are more susceptible todying over time in culture. In the experiments described in thisexample, this model system is used to interrogate new therapeuticapproaches to ameliorate TDP-43 toxicity.

Results

From the TDP-43 yeast model, a compound with known mode of action wasidentified that restored viability to TDP-43-expressing yeast (FIG. 1A).Fluconazole is an antifungal known to inhibit Erg11, the yeastlanosterol 14-alpha demethylase (FIG. 1B). Inhibition of Erg11 reducesergosterol synthesis (yeast equivalent of cholesterol), while increasinglanosterol levels, the substrate of Erg11 (FIG. 1C). The human homologof Erg11 is Cyp51A1, a member of the cytochrome P450 superfamily ofenzymes but does not appear to have a role in detoxification ofxenobiotics. CYP51A1 has also been known as lanosterol 14-alphademethylase, which describes its function in removing the14-alpha-methyl group from lanosterol to generate4,4-dimethylcholesta-8(9),14,24-trien-3β-ol, which is a critical step inthe cholesterol biosynthetic pathway.

To evaluate the potential role of CYP51A1 in TDP-43 pathology, theaforementioned primary rat cortical neuron TDP-43 models were utilizedto test the efficacy of published inhibitors (FIG. 2). Rat corticalneurons transfected with wild type human TDP-43 exhibited a significantreduction in survival compared to neurons transfected with empty vectorcontrol, and this reduction in survival was partially alleviated bytreatment with compound (3) (FIGS. 3A and 3B). A similar survival befitwas conferred by compound (3) when applied to cells transfected withQ331K mutant TDP-43 (FIGS. 4A and 4B). A similar effect in rescuing asurvival deficit was observed for a structurally differentiated compound(4) when applied to cells transfected with wild type TDP-43 (FIGS. 5Aand 5B). These studies demonstrate that inhibition of Erg11 in yeast andinhibition of Cyp51A1 has a beneficial effect of rescuing cells fromwild type and mutant TDP-43 toxicity and promotes cell survival. This isthe first demonstration that inhibition of CYP51A1 is beneficial intreating and preventing TDP-43 pathological processes and represents anovel therapeutic approach for the treatment of ALS.

Example 2. Use of a CYP51A1 Inhibitor for the Treatment or Prevention ofa Neurological Disorder in a Human Patient

Using the compositions and methods described herein, a patient sufferingfrom or at risk of developing a neurological disorder, such asamyotrophic lateral sclerosis, frontotemporal degeneration, Alzheimer'sdisease, Parkinson's disease, dementia with Lewy Bodies, corticobasaldegeneration, progressive supranuclear palsy, dementia parkinsonism ALScomplex of Guam, Huntington's disease, Inclusion body myopathy withearly-onset Paget disease and frontotemporal dementia (IBMPFD), sporadicinclusion body myositis, myofibrillar myopathy, dementia pugilistica,chronic traumatic encephalopathy, Alexander disease, or hereditaryinclusion body myopathy, may be administered a CYP51A1 inhibitor so asto treat the disease, alleviate one or more symptoms of the disease, orslow or prevent the onset of the disease. The CYP51A1 inhibitor may be,for example, a small molecule that specifically binds to an/or inhibitsthe enzymatic activity of CYP51A1, an antibody or antigen-bindingfragment thereof that specifically binds to and/or inhibits the activityof CYP51A1, or substance that reduces expression of functional CYP51A1,such as an interfering RNA molecule (for example, a siRNA, miRNA, orshRNA molecule described herein).

Prior to treatment, the patient may be subjected to one or moreanalytical tests in order to determine their initial quality of life,muscle strength, muscle function, slow vital capacity, decrementalresponses exhibited upon repetitive nerve stimulation, among otherparameters that describe the patient's initial disease state. Thepatient may then be administered a CYP51A1 inhibitor, such as by way oforal, transdermal, subcutaneous, intranasal, intravenous, intramuscular,intraocular, parenteral, topical, intrathecal, and/orintracerebroventricular administration. The CYP51A1 inhibitor may beadministered to the patient in combination with one or morepharmaceutically acceptable excipients, carriers, or diluents. TheCYP51A1 inhibitor may be administered to the patient once or a pluralityof times, such as periodically over the course of a treatment period ofone or more days, weeks, months, or years.

To determine the responsiveness of the patient to CYP51A1 inhibitortherapy, a physician may perform one or more tests in order to evaluatewhether the patient exhibits any of the following indications ofclinical benefit:

(i) an improvement in condition as assessed using the amyotrophiclateral sclerosis functional rating scale (ALSFRS) or the revised ALSFRS(ALSFRS-R);

(ii) an increase in slow vital capacity, such as an increase in thepatient's slow vital capacity within one or more days, weeks, or monthsfollowing administration of the CYP51A1 inhibitor;

(iii) a reduction in decremental responses exhibited by the patient uponrepetitive nerve stimulation, such as a reduction that is observedwithin one or more days, weeks, or months following administration ofthe CYP51A1 inhibitor;

(iv) an improvement in muscle strength, as assessed, for example, by wayof the Medical Research Council muscle testing scale (as described,e.g., in Jagtap et al., Ann. Indian. Acad. Neurol. 17:336-339 (2014),the disclosure of which is incorporated herein by reference as itpertains to measuring patient response to neurological diseasetreatment);

(v) an improvement in quality of life, as assessed, for example, usingthe amyotrophic lateral sclerosis-specific quality of life (ALS-specificQOL) questionnaire;

(vi) a decrease in the frequency and/or severity of muscle cramps, suchas a decrease in cramp frequency and/or severity within one or moredays, weeks, or months following administration of the CYP51A1inhibitor; and/or

(vii) a decrease in TDP-43 aggregation, such as a decrease in TDP-43aggregation within one or more days, weeks, or months followingadministration of the CYP51A1 inhibitor.

Example 3. Determining the Likelihood of a Patient to Respond to CYP51A1Inhibitor Therapy

Using the compositions and methods described herein, one may determinethe propensity of a patient (e.g., a human patient) suffering from aneurological disease to respond to CYP51A1 inhibitor therapy. Forexample, a physician may obtain a sample from a patient having aneurological disease, such as amyotrophic lateral sclerosis or anotherneurological disorder described herein. The physician may then determinewhether the patient expresses an isoform of TDP-43 having a mutationselected from Q331K, M337V, Q343R, N345K, R361S, and N390D, amongothers, as these mutations are associated with elevated TDP-43aggregation and toxicity. This may be done, for example, by determiningthe patient's genotype at the TDP-43 locus and/or by isolating TDP-43protein from a biological sample obtained from the patient andsequencing the protein using molecular biology techniques known in theart. A finding that the patient exhibits TDP-43 aggregation and/orexpresses a mutant TDP-43 protein having a Q331K, M337V, Q343R, N345K,R361S, or N390D mutation may be taken as an indication that the patientis likely to respond to CYP51A1 inhibitor therapy.

Upon determining that the patient is likely to respond to treatment witha CYP51A1 inhibitor, the patient may be administered one or more CYP51A1inhibitors, for example, as described in Example Two, above. Theinhibitor of CYP51A1 may be a small molecule, such as LEK-935,CP-320626, itraconazole, posaconazole, cyproconazole, voriconazole,fluconazole, clotrimazol, fenticonazole, epoxiconazole, ketoconazole,ravuconazole, isavuconazole, holothurin A, theasaponin, capsicosine,betulafolientriol, prochloraz, propiconazole, prothioconazole,prothioconazole-desthio, tebuconazole, triadimenol, azalanstat, or avariant thereof. In some embodiments, the CYP51A1 inhibitor is ananti-CYP51A1 antibody or antigen-binding fragment thereof, or acompound, such as an interfering RNA molecule, that attenuates CYP51A1expression.

OTHER EMBODIMENTS

All publications, patents, and patent applications mentioned in thisspecification are incorporated herein by reference to the same extent asif each independent publication or patent application was specificallyand individually indicated to be incorporated by reference.

While the invention has been described in connection with specificembodiments thereof, it will be understood that it is capable of furthermodifications and this application is intended to cover any variations,uses, or adaptations of the invention following, in general, theprinciples of the invention and including such departures from theinvention that come within known or customary practice within the art towhich the invention pertains and may be applied to the essentialfeatures hereinbefore set forth, and follows in the scope of the claims.

Other embodiments are within the claims.

What is claimed is:
 1. A method of treating a neurological disorderassociated with TDP-43 aggregation in a human patient, the methodcomprising administering to the patient a therapeutically effectiveamount of a CYP51A1 inhibitor represented by formula (XLIII):

wherein n is 2 or 3; p is 0, 1, or 2; q is 0, 1, or 2; X is oxygen orS(O)_(t) wherein t is 0, 1, or 2; each R₁ is independently halo, loweralkyl, lower alkoxy, or trifluoromethyl; each R₂ is independently haloor lower alkyl; R₃ is nitro or —N(R₅)R₆, where R₅ is hydrogen or loweralkyl, and R₆ is hydrogen, lower alkyl, lower alkylsulfonyl or —C(Y)R₇where Y is oxygen or sulfur and R₇ is hydrogen, lower alkyl, loweralkoxy or —N(R₈)R₉ where R₈ is hydrogen or lower alkyl and R₉ ishydrogen, lower alkyl or lower alkoxycarbonyl; or R₅ and R₆ togetherwith N is pyrrolidino, piperidino, morpholino, thiomorpholino orpiperazino, wherein the piperazino is optionally substituted at the4-position by —C(O)R₁₀ where R₁₀ is hydrogen, lower alkyl, lower alkoxyor amino; and R₄ is hydrogen or optionally substituted lower alkyl; or apharmaceutically acceptable salt thereof.
 2. The method of claim 1, themethod comprising: (i) determining that the patient is susceptible todeveloping TAR-DNA binding protein (TDP)-43 aggregation; and (ii)administering to the patient the therapeutically effective amount of theCYP51A1 inhibitor.
 3. The method of claim 1, wherein the patient haspreviously been determined to be susceptible to developing TDP-43aggregation.
 4. The method of claim 1, the method comprising: (i)determining that the patient expresses a mutant form of TDP-43 having amutation associated with TDP-43 aggregation; and (ii) administering tothe patient the therapeutically effective amount of the CYP51A1inhibitor.
 5. The method of claim 1, wherein the patient has previouslybeen determined to express a mutant form of TDP-43 having a mutationassociated with TDP-43 aggregation.
 6. The method of claim 5, whereinthe mutation is selected from the group consisting of Q331K, M337V,Q343R, N345K, R361S, and N390D.
 7. The method of claim 1, wherein theneuromuscular disorder is amyotrophic lateral sclerosis.
 8. The methodof claim 1, wherein the CYP51A1 inhibitor is azalanstat.